Benzimidazolidinone derivatives as muscarinic agents

ABSTRACT

Benzimidazolidinone derivative compounds, which increase acetylcholine signaling or effect in the brain, and highly selective muscarinic agonists, particularly for the M 1  and/or M 4  receptor subtypes, pharmaceutical compositions comprising the same, as well as methods of treating psychosis using these compounds are disclosed.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.10/262,517, filed Sep. 30, 2002, which claims priority to U.S.Provisional Patent Application Ser. No. 60/326,754, filed Oct. 2, 2001,both of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

Novel benzimidazolidinone derivatives have been prepared and identifiedas having high affinity for muscarinic M₁ and M₄ receptors. Thetreatment of mental disorders associated with increasing the activity ofa cholinergic receptor using these novel compounds is anticipated.Moreover, these compounds also have dopamine D₂ antagonist activity,rendering them particularly interesting as anti-psychotic agents.

BACKGROUND OF THE INVENTION

Muscarinic cholinergic receptors mediate the actions of theneurotransmitter acetylcholine in the central and peripheral nervoussystems. Muscarinic receptors play a critical role in the centralnervous system mediating higher cognitive functions, as well as in theperipheral parasympathetic nervous system where they mediate cardiac,respiratory, digestive, and endocrine and exocrine responses. Fivedistinct muscarinic receptor subtypes have been identified, M₁-M₅. Themuscarinic M₁ receptor subtype is predominantly expressed in thecerebral cortex and is believed to be involved in the control of highercognitive functions; the M₂ receptor is the predominant subtype found inheart and is involved in the control of heart rate; the M₃ receptor iswidely expressed in many peripheral tissues and is believed to beinvolved in gastrointestinal and urinary tract stimulation as well assweating and salivation; the M₄ receptor is present in brain and may beinvolved in locomotion; the M₅, receptor is present in the brain whereits role is at present poorly defined. M₁ and M₄ have been particularlyassociated with the dopaminergic system.

Conditions associated with cognitive impairment, such as Alzheimer'sdisease, are accompanied by a reduction of acetylcholine content in thebrain. This is believed to be the result of degeneration of cholinergicneurons of the basal forebrain, which widely innervate multiple areas ofthe brain, including the association cortices and hippocampus, that arecritically involved in higher processes.

Efforts to increase acetylcholine levels have focused on increasinglevels of choline, the precursor for acetylcholine synthesis, and onblocking acetylcholineesterase (AChE), the enzyme that metabolizesacetylcholine. Attempts to augment central cholinergic function throughthe administration of choline or phosphatidylcholine have not beensuccessful. AChE inhibitors have shown therapeutic efficacy, but havebeen found to have frequent cholinergic side effects due to peripheralacetylcholine stimulation, including abdominal cramps, nausea, vomiting,and diarrhea. These gastrointestinal side effects have been observed inabout a third of the patients treated. In addition, some AChEinhibitors, such as tacrine, have also been found to cause significanthepatotoxicity with elevated liver transaminases observed in about 30%of patients. The adverse effects of AChE inhibitors have severelylimited their clinical utility.

The dopamine hypothesis of schizophrenia suggests that increaseddopamine neurotransmission underlies the positive symptoms of thedisease and is supported by the evidence that dopamine receptor blockadeis effective in ameliorating such psychotic symptoms. Further, drugsthat enhance dopamine neurotransmission in the brain causepsychotic-like episodes in man and exacerbate psychotic symptoms inschizophrenic patients. In animal studies, drugs that increase dopamineneurotransmission cause behavioural effects such as increasedlocomotion, climbing and deficits in prepulse inhibition. Knownantipsychotics and dopamine receptor antagonists can block thesebehavioural effects. Unfortunately, dopamine receptor antagonists alsocause severe extrapyramidal side effects in patients as predicted byinduction of catalepsy in animal models. These extrapyramidal sideeffects include tremor, bradykinesia, akithesias, and tardivedyskinesias.

Due in part to these observations, the discovery of agents with M₁receptor agonist activity has been sought after for the treatment ofdementia. However, existing agents lack specificity in their actions atthe various muscarinic receptor subtypes. Known M₁ muscarinic agonistssuch as arecoline have also been found to be weak agonists of M₂ as wellas M₃ receptor subtypes and are ineffective in the treatment ofcognitive impairment, due in large part to their dose-limiting M₂ and M₃receptor mediated side effects.

Xanomeline (Shannon et al., J. Pharmacol. Exp. Ther. 1994, 269, 271;Shannon et al., Schizophrenia Res. 2000, 42, 249) is an M₁/M₄ preferringmuscarinic receptor agonist with little or no affinity for dopaminereceptors despite inhibiting A10 but not A9 dopamine cells. Thethiadiazole derivative PTAC has been reported (Shannon et al., EuropeanJournal of Pharmacology, 1998, 356, 109) to have partial agonist effectat muscarinic M₂ and M₄ receptors and antagonist effect at muscarinicM₁, M₃, and M₅ receptors as well as exhibiting functional dopamineantagonism.

Recently, muscarinic agonists including xanomeline have been shown to beactive in animal models with similar profiles to known antipsychoticdrugs, but without causing catalepsy (Bymaster et al., Eur. J.Pharmacol. 1998, 356, 109, Bymaster et al., Life Sci. 1999, 64, 527,Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901, Shannon et al.,Schizophrenia Res. 2000, 42, 249). Further, xanomeline was shown toreduce psychotic behavioural symptoms such as delusions, suspiciousness,vocal outbursts, and hallucinations in Alzheimer's disease patients(Bodick et al., Arch. Neurol. 1997, 54, 465), however treatment inducedside effects that severely limit the clinical utility of this compound.

Analogues of 1,2,5-thiadiazole have been reported (Sauerberg et al., J.Med. Chem. 1998, 41, 4378) to have high affinity and selectivity forcentral muscarinic receptors as well as exhibiting functional dopamineantagonism despite lack of affinity for dopamine receptors.

The present investigators have focussed their efforts on the developmentof a molecule that simultaneously reduced the positive symptoms andimproved the negative symptoms and the cognitive impairments associatedwith schizophrenia as a novel treatment of mental disorders. It is theintent of the present investigators to demonstrate that muscarinic M₁and/or M₄ agonists with combined D₂ antagonist activity may possesssuperior antipsychotic efficacy without the side effects associated withhigh dose D₂ antagonism alone. The D₂ antagonist properties of thesemolecules may contribute to a reduction in the positive symptoms of thisdisease.

Based on distribution of M₁ and M₄ receptors in the cerebral cortex andhippocampus (the areas involved in higher order cognitive functions),the M₁ and/or M₄ agonist properties of these compounds may reduce thecognitive dulling and perhaps ameliorate other negative symptomsassociated with schizophrenia. (Friedman, Biol. Psychiatry, 1999, 45, 1;Rowley, J. Med. Chem. 2001, 44, 477; Felder, J. Med. Chem. 2000, 43,4333). This unique combination of central nervous system activities inone molecule is unprecedented and may lead to the development of anentirely new class of antipsychotic drugs, ones with the superiorclinical properties without the limiting side-effect profile.

WO 99/32481 discloses derivatives including 1-substitutedbenzimidazolones and derivatives thereof. The compounds according to WO99/32481 are intended for treatment of glaucoma, myopia, psychosis andvarious other conditions involving muscarinic receptors.

U.S. Pat. No. 4,254,127 discloses 1-(1-piperidinyl)alkyl-benzimidazolonederivatives wherein the piperidine is 4-substituted with aryl-alkyls,aryl-alkylcarbonyls, aryl-alkylcarbonyl derivatives, and aryl-alkoxides.The compounds according to U.S. Pat. No. 4,254,127 are reported to havepsychotropic activity acting as serotonin antagonists.

U.S. Pat. No. 5,789,425 and U.S. Pat. No. 5,726,188 discloses1-substituted imidazolidin-2-one derivatives with muscarinic M₁activity. Benzimidazolidinone derivatives are not disclosed therein.

WO 96/13262 disclose benzimidazolidin-2-one derivatives 1-subsitutedwith a 4-piperidinyl moiety which in turn is 1-substituted. Thecompounds according to WO 96/13262 are reported to have anti-muscarinicactivity intended for the treatment of myopia. Benzimidazolidin-2-onederivatives 1-subsituted with moieties other than a 4-piperidinyl groupis not disclosed.

WO 97/16192, WO 97/16187 and U.S. Pat. No. 5,756,508 disclose novel1,3-dihydro[1-(1-heteroarylpiperidine-4-yl)piperidine-4-yl]-2H-benzimidazolones.The compounds according to WO 97/16192, WO 97/16187 and U.S. Pat. No.5,756,508 are reported to have antimuscarinic activity used fortreatment and/or prevention of myopia.

WO 97/16186 and U.S. Pat. No. 5,718,912 disclose1-[cycloalkylpiperidin-4-yl]-2H-benzimidazolones as selective muscarinicagonists of the M₂ subtype with low activity at the M₃ subtype, and whenutilised for glaucoma therapy have fewer side effects than pilocarpinetherapy.

Cakir, B et al. describes the synthesis and antinociceptive activity ofsome 1-(3-piperidinopropyl)benzothiazolone derivatives in Farmaco, 1999,54, 846.

There is a need in the art to provide compounds that increaseacetylcholine signaling or effect in the brain. Specifically there is aneed for muscarinic agonists that are active at various muscarinicreceptor subtypes in the central and peripheral nervous system. There isa further need to develop more highly selective muscarinic agonists,such as M₁ and/or M₄ selective agents, both as pharmacological tools andas potential therapeutic agents. Moreover, there is a need for compoundsaimed at the approach of treating psychosis using compounds which has acombined muscarinic agonist and dopamine antagonist profile.

SUMMARY OF THE INVENTION

The present invention seeks to provide compounds which increaseacetylcholine signaling or effect in the brain, and highly selectivemuscarinic agonists, particularly for the M₁ and/or M₄ receptor subtypesas well as providing compounds aimed at the approach of treatingpsychosis using compounds which has a combined muscarinic agonist anddopamine antagonist profile.

In a first aspect, the present invention relates to a compound ofFormula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X is selected from the group consisting of C, O, N and S

Z is selected from the group consisting of CH and N

Y is selected from the group consisting of ═O, ═N and ═S or tautomersthereof, such as Y-alkylated tautomers;

SPU is a spacer unit providing a distance d between Z and N wherein

-   -   —SPU— is a biradical selected from the group consisting of        —(CR⁶R⁷)_(n)-A- and —C₃₋₈-cycloalkyl-    -   wherein n is in the range 1 to 5, such as 1, 2, 3, 4, or 5 and    -   A is absent or an optionally substituted —C₃₋₈-cycloalkyl;

N together with R¹ and R² form a heterocyclic ring wherein saidheterocyclic ring is selected from the group consisting ofperhydroazocine, perhydroazepine, piperidine, pyrrolidine, azetidine,aziridine and 8-azabicyclo[3.2.1]octane

and wherein the heterocyclic ring is substituted with one or moresubstituents R⁴ selected from the group consisting of hydroxy, halogen,C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl,C₁₋₈-alkylidene, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₆-alkyloxyimino, andC₁₋₆-alkyloxyamino each of which may be optionally substituted with asubstituent R⁵

and wherein at least one of said substituents R⁴ is R⁴ selected from thegroup consisting of C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy,C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidenec C₁₋₈-alkyloxyimino, andC₁₋₈-alkyloxyamino each of which may be optionally substituted with asubstituent R⁵;

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₈-alkyl, C₁₋₈-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl and C₂₋₈-alkynyl;

R^(X) may be absent or selected from the group consisting of hydrogen,optionally substituted C₁₋₈-alkyl, optionally substitutedC₃₋₈-cycloalkyl, optionally substituted C₂₋₈-alkenyl, optionallysubstituted C₂₋₈-alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl CH₂—N(R⁵)(R⁵), CH₂—OR⁵, CH₂—SR⁵, CH₂—O—C(═O)R⁵,CH₂—O—C(═S)R⁵;

R³ may be present 0-4 times and selected from the group consisting ofhalogen, hydroxy, optionally substituted C₁₋₈-alkyl, C₁₋₈-alkoxy,optionally substituted C₁₋₈-alkylidene, optionally substitutedC₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedC₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl, andoptionally substituted C₁₋₈-alkylcarbonyl;

each R⁶ and each R⁷ is independently selected from the group consistingof hydrogen, halogen, hydroxy, optionally substituted C₁₋₈-alkyl,C₁₋₈-alkoxy, optionally substituted C₁₋₈-alkylidene, optionallysubstituted C₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted C₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl,and optionally substituted C₁₋₈-alkylcarbonyl.

A second aspect of the invention relates to a method of increasing anactivity of a cholinergic receptor comprising contacting the cholinergicreceptor or a system containing the cholinergic receptor with aneffective amount of at least one compound of Formula I.

An increase in activity of the cholinergic receptor and the cholinergicsystem is, as discussed supra, associated to the activity ofanti-psychotics. Accordingly, further aspects of the present inventionrelate to a method of treating or preventing a mental disorder in amammal, comprising the administration of an effective amount of acompound of Formula I and to the use of a compound of Formula I, apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition containing either entity, for the preparation of amedicament for the prophylactic or curative treatment of psychosis oralleviation of symptoms of psychosis. In the context of the presentinvention a mammal may be selected from the group consisting of mice,rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates,such as monkeys, chimpanzees, and apes, and humans. Most preferably, themammal is a human.

Aspects of the invention relate to compounds of Formula I for use asselective modulators of M₁ and/or M₄ muscarinic receptors for thetreatment of disorders associated with muscarinic receptors andespecially with said receptor subtypes.

As stated, compounds of Formula I have surprisingly been found to haveselectivity for the M₁ and M₄ muscarinic receptor subtypes. Therapeuticadvantages may be derived from this selectivity. Further therapeuticadvantages may be derived from the concomitant muscarinic M₁ and M₄agonist activity and dopaminergic D₂ antagonist activity.

Compounds of Formula I, by the modulation of muscarinic receptors may beimplicated in the control of amyloid precursor processing, in particularby the activation of the M₁ receptor. Thus, a further aspect of thepresent invention relates to a method of modulating or preventing theprogression or formation of amyloid plaques in an individual susceptibleto or affected by Alzheimer's Disease by administering an effectiveamount of a compound of Formula I, said effective amount sufficient tomodulate amyloid precursor protein processing.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph depicting the reduction of spontaneous locomotoractivity in mice with the administration of 10 mg/kg i.p. of 61KS19.

FIG. 2 is a graph that shows the reduction of amphetamine-inducedhyperactivity in mice with the administration of 3 and 10 mg/kg i.p. of61KS19

FIG. 3 is a graph that shows the reduction of scopolamine-inducedhyperactivity in mice with the administration of 1, 3 and 10 mg/kg i.p.of 61KS19

FIG. 4 is a graph that shows the reduction of MK-801-inducedhyperactivity in mice with the administration of 10 mg/kg i.p. of61KS19.

FIG. 5 depicts the result of a comparison between haloperidol and61KS19, and shows that unlike haloperidol, 61KS19 (10 mg/kg i.p.) failedto induce catalepsy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a first aspect, the present invention relates to a compound ofFormula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X is selected from the group consisting of C, O, N and S

Z is selected from the group consisting of C and N

Y is selected from the group consisting of ═O, ═N and ═S or tautomersthereof, such as Y-alkylated tautomers;

SPU is a spacer unit providing a distance d between Z and N wherein

-   -   —SPU— is a biradical selected from the group consisting of        —(CR⁶R⁷)_(n)-A- and —C₃₋₈-cycloalkyl-    -   wherein n is in the range 1 to 5, such as 1, 2, 3, 4, or 5 and    -   A is absent or an optionally substituted —C₃₋₈-cycloalkyl;

N together with R¹ and R² form a heterocyclic ring wherein saidheterocyclic ring is selected from the group consisting ofperhydroazocine, perhydroazepine, piperidine, pyrrolidine, azetidine,aziridine and 8-azabicyclo[3.2.1]octane

and wherein the heterocyclic ring is substituted with one or moresubstituents R⁴ selected from the group consisting of hydroxy, halogen,C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl,C₁₋₈-alkylidene, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₆-alkyloxyimino, andC₁₋₆-alkyloxyamino each of which may be optionally substituted with asubstituent R⁵

and wherein at least one of said substituents R⁴ is R^(4′) selected fromthe group consisting of C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy,C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidenec C₁₋₈-alkyloxyimino, andC₁₋₈-alkyloxyamino each of which may be optionally substituted with asubstituent R⁵;

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, C₁₋₈-alkylcarbonyl,C₁₋₈-alkylidene, C₂₋₈-alkenyl and C₂₋₈-alkynyl;

R^(X) may be absent or selected from the group consisting of hydrogen,optionally substituted C₁₋₈-alkyl, optionally substitutedC₃₋₈-cycloalkyl, optionally substituted C₂₋₈-alkenyl, optionallysubstituted C₂₋₈-alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, CH₂—N(R⁵)(R⁵), CH₂—OR⁵, CH₂—SR⁵, CH₂—O—C(═O)R⁵,CH₂—O—C(═S)R⁵;

R³ may be present 0-4 times and selected from the group consisting ofhalogen, hydroxy, optionally substituted C₁₋₈-alkyl, C₁₋₈-alkoxy,optionally substituted C₁₋₈-alkylidene, optionally substitutedC₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedC₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl, andoptionally substituted C₁₋₈-alkylcarbonyl;

each R⁶ and each R⁷ is independently selected from the group consistingof hydrogen, halogen, hydroxy, optionally substituted C₁₋₈-alkyl,C₁₋₈-alkoxy, optionally substituted C₁₋₈-alkylidene, optionallysubstituted C₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted C₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl,and optionally substituted C₁₋₈-alkylcarbonyl.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the invention with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the invention witha base to form a salt such as an ammonium salt, an alkali metal salt,such as a sodium or a potassium salt, an alkaline earth metal salt, suchas a calcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound of the present invention which is administered as an ester(the “prodrug”) to facilitate transmittal across a cell membrane wherewater solubility is detrimental to mobility but which then ismetabolically hydrolyzed to the carboxylic acid, the active entity, onceinside the cell where water-solubility is beneficial. A further exampleof a prodrug might be a short peptide (polyaminoacid) bonded to an acidgroup where the peptide is metabolized to reveal the active moiety.

The term “selective” or “selectivity” is intended to mean the ability ofa compound to generate a desired response from a particular receptortype, subtype, class or subclass while generating less or littleresponse from other receptor types. “Selective” or “selectivity” of anM₁ or M₄ muscarinic agonist compound is intended to mean the ability ofa compound to increase the activity of the M₁ or M₄ muscarinic receptor,respectively, while causing non-substantial, little or no increase inthe activity of other subtypes including M₃ and M₅ subtypes, andpreferably the M₂ subtype. Compounds of the presents invention may alsoshow selectivity toward both M₁ and M₄ receptors, i.e. increase theactivity of both the M₁ and M₄ muscarinic receptors, while causinglittle or no increase in the activity of other subtypes including M₃ andM₅ subtypes, and preferably the M₂ subtype.

In the present context, the term “C₁₋₈-alkyl” is intended to mean alinear or branched saturated hydrocarbon chain wherein the longestchains has from one to eight carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, heptyl and octyl. A branched hydrocarbonchain is intended to mean a C₁₋₈-alkyl substituted at any carbon with ahydrocarbon chain.

In the present context, the term “C₂₋₈-alkenyl” is intended to mean alinear or branched hydrocarbon group having from two to eight carbonatoms and containing one or more double bonds. Illustrative examples ofC₂₋₈-alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl,pentenyl, hexenyl, heptenyl and octenyl. Illustrative examples ofC₂₋₁₀-alkenyl groups with more than one double bond include butadienyl,pentadienyl, hexadienyl, heptadienyl, hexatrienyl, heptatrienyl andoctatrienyl groups as well as branched forms of these. The position ofthe unsaturation (the double bond) may be at any position along thecarbon chain.

In the present context, the term “C₁₋₈-alkylidene” is intended to mean alinear or branched hydrocarbon chain radical wherein the longest chainhas from one to eight carbon atoms and an unsaturated bond at theradical position. Bonds further than the radical position may also beunsaturated.

In the present context the term “C₂₋₈-alkynyl” is intended to meanlinear or branched hydrocarbon groups containing from two to eightcarbon atoms and containing one or more triple bonds. Illustrativeexamples of C₂₋₈-alkynyl groups include ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl and octynyl groups as well as branched formsof these. The position of unsaturation (the triple bond) may be at anyposition along the carbon chain. More than one bond may be unsaturatedsuch that the “C₂₋₈-alkynyl” is a di-yne or enedi-yne as is known to theperson skilled in the art.

In the present context the term “C₃₋₈-cycloalkyl” is intended to coverthree-, four-, five-, six- seven-, and eight-membered rings comprisingcarbon atoms only whereas the term “heterocyclyl” is intended to meanthree-, four-, five-, six- seven-, and eight-membered rings whereincarbon atoms together with from 1 to 3 heteroatoms constitute said ring.The heteroatoms are independently selected from oxygen, sulphur, andnitrogen.

C₃₋₈-cycloalkyl and heterocyclyl rings may optionally contain one ormore unsaturated bonds situated in such a way, however, that an aromatic1-electron system does not arise.

Illustrative examples of preferred “C₃₋₈-cycloalkyl” are the carbocyclescyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,cycloheptane, cycloheptene, 1,2-cycloheptadiene, 1,3-cycloheptadiene,1,4-cycloheptadiene and 1,3,5 cycloheptatriene.

Illustrative examples of “heterocyclyls” are the heterocycles2H-thipyran, 3H-thipyran, 4H-thipyran, tetrahydrothiopyran, 2H-pyran,4H-pyran, tetrahydropyran, piperidine, 1,2-dithiin, 1,2-dithiane,1,3-dithiin, 1,3-dithiane, 1,4-dithiin, 1,4-dithiane, 1,2-dioxin,1,2-dioxane, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,2-oxathiin, 1,2-oxathiane, 4H-1,3-oxathiin, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, 2H-1,2-thiazine, tetrahydro-1,2-thiazine,2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-thiazine,4H-1,4-thiazine, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,4H-1,2-oxazine, 6H-1,2-oxazine, 2H1,3-oxazine, 4H-1,3-oxazine,4H-1,4-oxazine, maleimide, succinimide, dioxopiperazine, hydantoin,morpholine, trioxane, 4H-1,2,3-trithiin, 1,2,3-trithiane,1,3,5-trithiane, hexahydro-1,3,5-triazine, tetrahydrothiophene,tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione,pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,2-dioxole,1,2-dioxolane, 1,3-dioxole, 1,3-dioxolane, 3H-1,2-dithiole,1,2-dithiolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline,isoxazolidine, oxazoline, oxazolidine, thiazoline, thiozolidine,3H-1,2-oxathiole, 1,2-oxathiolane, 5H-1,2-oxathiole, 1,3-oxathiole,1,3-oxathiolane, 1,2,3-trithiole, 1,2,3-trithiolane, 1,2,4-trithiolane,1,2,3-trioxole, 1,2,3-trioxolane, 1,2,4-trioxolane, 1,2,3-triazoline and1,2,3-triazolidine. Binding to the heterocycle may be at the position ofthe heteroatom or via carbon atom of the heterocycle.

In the present context the term “aryl” is intended to mean a carbocyclicaromatic ring or ring system. Moreover, the term “aryl” includes fusedring systems wherein at least two aryl rings, or at least one aryl andat least one C₃₋₈-cycloalkyl, or at least one aryl and at least oneheterocyclyl, share at least chemical bond. Illustrative examples of“aryl” rings include optionally substituted phenyl, naphthalenyl,phenanthrenyl, anthracenyl, acenaphthylenyl, tetralinyl, fluorenyl,indenyl, indolyl, coumaranyl, coumarinyl, chromanyl, isochromanyl, andazulenyl. A preferred aryl group is phenyl.

In the present context, the term “heteroaryl” is intended to mean anaryl group where one or more carbon atoms in an aromatic ring have beenreplaced with one or more heteroatoms selected from the group comprisingnitrogen, sulphur, phosphorous and oxygen.

Furthermore, in the present context, the term “heteroaryl” comprisesfused ring systems wherein at least one aryl ring and at least oneheteroaryl ring, at least two heteroaryls, at least one heteroaryl andat least one heterocyclyl, or at least one heteroaryl and at least oneC₃₋₈-cycloalkyl share at least one chemical bond, such as one or twochemical bonds.

Illustrative examples of a heteroaryl may be selected from the groupcomprising furanyl, thienyl, pyrrolyl, phenoxazonyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, isoxazolyl, imidazolylisothiazolyl, oxadiazolyl, furazanyl, triazolyl, thiadiazolyl,piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyland triazinyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl,benzopyrazolyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl,quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinylthienofuranyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl andthianthrenyl.

When used herein the term “C₁₋₈-alkoxy” is intended to meanC₁₋₈-alkyl-oxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy andhexoxy

The term “halogen” includes fluorine, chlorine, bromine and iodine.

In the present context, i.e. in connection with the terms “aryl”,“heteroaryl”, “C₃₋₈-cycloalkyl”, “heterocyclyl”, “C₁₋₈-alkyl”,“C₁₋₈-alkoxy”, “C₂₋₈-alkenyl”, and “C₂₋₈-alkynyl”, the term “optionallysubstituted” is intended to mean that the group in question may besubstituted one or several times, such as 1 to 5 times, preferably 1 to3 times, most preferably 1 to 2 times, with one or more groups selectedfrom C₁₋₈-alkyl, C₁₋₈-alkoxy, oxo (which may be represented in thetautomeric enol form), carboxyl, amino, hydroxy (which when present inan enol system may be represented in the tautomeric keto form), nitro,sulphono, sulphanyl, C₁₋₈-carboxyl, C₁₋₈-alkoxycarbonyl,C₁₋₈-alkylcarbonyl, formyl, aryl, aryloxy, aryloxycarbonyl,arylcarbonyl, heteroaryl, amino, mono- and di(C₁₋₈-alkyl)amino;carbamoyl, mono- and di(C₁₋₈-alkyl)aminocarbonyl,amino-C₁₋₈-alkyl-aminocarbonyl, mono- anddi(C₁₋₈-alkyl)amino-C₁₋₈-alkyl-aminocarbonyl, C₁₋₈-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₈-alkanoyloxy, C₁₋₈-alkylsulphonyloxy,dihalogen-C₁₋₈-alkyl, trihalogen-C₁₋₈-alkyl, halogen, where aryl andheteroaryl representing substituents may be substituted 1-3 times withC₁₋₈-alkyl, C₁₋₈-alkoxy, nitro, cyano, hydroxy, amino or halogen. Ingeneral, the above substituents may be susceptible to further optionalsubstitution.

The term “salts” is intended to mean pharmaceutically acceptable acidaddition salts obtainable by treating the base form of a functionalgroup, such as an amine, with appropriate acids such as inorganic acids,for example hydrohalic acids; typically hydrochloric, hydrobromic,hydrofluoric, or hydroiodic acid; sulfuric acid; nitric acid; phosphoricacid and the like; or organic acids, for example acetic, propionic,hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methane sulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic acid, cyclohexanesulfamic,2-hydoxybenzoic, 4-amino-2-hydroxybenzoic, ethanedisulfonic, and otheracids known to the skilled practitioner.

In certain embodiments of the present invention, the spacer unit SPUcomprises a number of optionally substituted methylene groups CR⁶R⁷. Itis understood by the phrase “each R⁶ and each R⁷ is optionally andindependently selected” that not all R⁶ groups may be identical and notall R⁷ groups may be identical. Thus, each substituted methylene groupmay have an R⁶ and an R⁷ that is different than any other R⁶ or R⁷substituents on other methylene groups. In some embodiments, some of R⁶or R⁷ substituents may be identical in one or more methylene groups.

In one embodiment, the present invention relates to a compound ofFormula I, wherein

X is selected from the group consisting of O, N and S;

Z is N

Y is ═O or tautomers thereof;

SPU is a spacer unit providing a distance d between Z and N wherein—SPU— is —(CR⁶R⁷)_(n)-A-, n is 3, and A is absent;

N together with R¹ and R² form a piperidine ring substituted with one ormore substituents R⁴ selected from the group consisting of hydroxy,halogen, C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl,C₁₋₈-alkylidene, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₆-alkyloxyimino, andC₁₋₆-alkyloxyamino each of which may be optionally substituted with asubstituent R⁵

and wherein at least one of said substituents R⁴ is R^(4′) selected fromthe group consisting of C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy,C₁₋₈-alkylidenec, each of which may be optionally substituted with asubstituent R⁵;

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₈-alkyl, C₁₋₈-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl and C₂₋₈-alkynyl;

R^(X) may be absent or selected from the group consisting of hydrogen,optionally substituted C₁₋₈-alkyl;

R³ may be present 0-4 times and selected from the group consisting ofhalogen, hydroxy, optionally substituted C₁₋₈-alkyl, C₁₋₈-alkoxy,optionally substituted C₁₋₈-alkylidene, optionally substitutedC₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedC₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl, andoptionally substituted C₁₋₈-alkylcarbonyl; and

each R⁶ and each R⁷ is optionally and independently selected from thegroup consisting of hydrogen, halogen, hydroxy, optionally substitutedC₁₋₈-alkyl, C₃₋₈-cycloalkyl,

In certain embodiments of compound of Formula I, Z is N (nitrogen).Thus, the distance d relates to the distance between the ring nitrogenatom and the nitrogen atom of N(R¹)R².

In compounds of Formula I, X may be selected from the group consistingof N, S, and O, preferably N and O. In a preferred embodiment X and Zare both N.

In a suitable embodiment of compounds of Formula I, —Y is selected fromthe group consisting of ═O, ═S and tautomers thereof. Tautomers of thecarbonyl and thiocarbonyl moiety are known to the person skilled in theart and are isomers involving migration of the pi system from theexo-cyclic to the endocyclic position. The enolic or thio-enolicderivative may be O- or S-alkylated in a manner known to the personskilled in the art.

In a preferred embodiment however, —Y is ═O or its tautomer. Preferably—Y is ═O. Thus, in a combination of preferred embodiments, X is N, —Y is═O, and Z is N, resulting in a benzimidazolidinone ring system.

The moiety Z is substituted with a spacer unit (SPU). SPU provides adistance d between Z and N. The distance d is formed from a short,optionally substituted aliphatic chain, (CR⁶R⁷)_(n), wherein n is in therange 1 to 5, such as 1, 2, 3, 4 or 5 or from said chain and a—C₃₋₈-cycloalkyl-ring. Thus, d may be defined in terms of through-bonddistances between Z and N of N(R¹)R² or a combination of through-bondand through-space distances between Z and N of N(R¹)R². Thus, —SPU— is abiradical selected from the group consisting of —(CR⁶R⁷)_(n)-A- and—C₃₋₈-cycloalkyl- wherein n is in the range 1 to 5 and

A is absent or an optionally substituted —C₃₋₈-cycloalkyl. Preferably, nis in the range 2 to 5, most preferably 2 to 4, such as 2, 3, or 4.

In an interesting embodiment of the present invention, theC₃₋₈-cycloalkyl-ring of —SPU— is an optionally substitutedcyclohexylene. Thus, —SPU— may be selected from the group consisting of—(CR⁴R⁵)_(n)-A- and an optionally substituted cyclohexylene wherein n isin the range 1 to 5, preferably 2 to 5 and A is absent or an optionallysubstituted cyclohexylene.

In an interesting embodiment, —SPU— is an ethylene, propylene, butylene,or pentylene biradical, preferably ethylene, propylene or butylene, eachof which may be optionally substituted. Alternatively, —SPU— is acylcohexylene biradical.

The cyclohexylene of —SPU— may be an optionally substituted1,3-cyclohexylene or an optionally substituted 1,4-cyclohexylene,preferably an optionally substituted 1,4-cyclohexylene. That is to saythat in the embodiment where SPU is or comprises of a cyclohexylene,said cyclohexylene is preferably bond to Z and N at positions 1 and 4 or1 and 3 of said ring.

As stated, N together with R¹ and R² form a heterocyclic ring whereinsaid heterocyclic ring is selected from the group consisting ofperhydroazocine, perhydroazepine, piperidine, pyrrolidine, azetidine,aziridine and 8-azabicyclo[3.2.1]octane. In a preferred embodiment,N(R¹)R² is selected from the group consisting of a piperidine,pyrrolidine, and azetidine, most preferably piperidine and pyrrolidine,particularly preferably piperidine.

The heterocyclic ring formed by N together with R¹ and R² is substitutedwith one or more substituents R⁴ selected from the group consisting ofhydroxy, halogen, C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy,C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkyloxyimino, and C₁₋₈-alkyloxyamino each of which may beoptionally substituted with a substituent R⁵ and at least one of saidsubstituents R⁴ is R⁴ selected from the group consisting of C₁₋₈-alkyl,C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₈-alkyloxyimino, and C₁₋₈-alkyloxyaminoeach of which may be optionally substituted with a substituent R⁵.

Thus, the heterocyclic ring formed by N together with R¹ and R² may besubstituted with one or more substituent R⁴ wherein at least one R⁴ isR^(4′).

As stated, the heterocyclic ring formed by N together with R¹ and R² issubstituted with one more substituent R⁴. In a preferred embodiment, theheterocyclic ring is selected from the group comprising of a piperidinewith at least one substituent R^(4′) in the 2-position, a piperidinewith at least one substituent R^(4′) in the 3-position, a piperidinewith at least one substituent R^(4′) in the 4-position, a pyrrolidinewith at least one substituent R^(4′) in the 3-position, an azetidinewith at least one substituent R^(4′) in the 3-position and an aziridinewith at least one substituent R^(4′) in the 2-position.

In a particularly suitable embodiment, N(R¹)R² is selected from thegroup consisting of a piperidine with at least one substituent R^(4′) inthe 2-position, a piperidine with at least one substituent R⁴ in the3-position, a piperidine with at least one substituent R^(4′) in the4-position, most preferably consisting of a piperidine with at least onesubstituent R^(4′) in the 4-position.

In the preferred embodiment wherein N together with R¹ and R² form apiperidine with at least one substituent R^(4′) in the 4-position,N(R¹)R² may be defined as

wherein R⁴ is selected from the group consisting of hydrogen, hydroxy,halogen, C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl,C₁₋₈-alkylidene, C₂₋₈-alkenyl, and C₂₋₈-alkynyl each of which may beoptionally substituted with a substituent R⁵and wherein R^(4′) is selected from the group consisting of C₁₋₈-alkyl,C₃₋₈-cycloalkyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl, and C₂₋₈-alkynyl each ofwhich may be optionally substituted with a substituent R⁵; andR⁵ is selected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl andC₂₋₈-alkynyl.

In a preferred embodiment, R⁴ is selected from the group consisting ofhydrogen, hydroxy and halogen most preferably hydrogen and hydroxy andR⁵ substituted C₁₋₈-alkyl.

The one or more substituent R^(4′) may be selected from the groupconsisting of C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkylidene, each ofwhich may be optionally substituted with a substituent R⁵. In acombination of preferred embodiments, the one or more substituent R⁴ maybe selected from the group consisting of a C₁₋₈-alkyl, andC₃₋₈-alkylidene, each of which may be optionally substituted with asubstituent R⁵ wherein R⁵ is selected from the group consisting ofhydrogen, halogen, hydroxy, C₁₋₈-alkyl and C₃₋₈-cycloalkyl.

Most preferably, R⁵ is selected from the group consisting of hydrogen,halogen, hydroxy, C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl,C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl and C₂₋₈-alkynyl,particularly hydrogen, hydroxy, halogen and C₁₋₈-alkyl.

In a particularly preferred embodiment, R⁴ is selected from the groupconsisting of propyl, propylidene, butyl, butylidene, pentyl andpentylidene, each of which may be optionally substituted. In a mostpreferred embodiment, R⁴ is selected from the group consisting of butyl,a pentyl and 3-(C₁₋₈-alkyl)-butylidene, each of which may be optionallysubstituted.

As will be clear to the person skilled in the art, embodiments ofcompound I may be chiral or comprised of one or more chiral centres.Where the compounds according to the invention have at least one chiralcenter, they may exist as a racemate, enantiomers or diastermeomers. Itshould be noted that all such isomers and mixtures thereof are includedin the scope of the present invention. Furthermore, some of thecrystalline forms for compounds of the present invention may exist aspolymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds of the present inventionmay form solvates with water (i.e. hydrates) or common organic solvents.Such solvates are also included in the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, such isomers maybe separated by conventional techniques such as preparative chiralchromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by stereoselectivesynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary or desirable to protect sensitiveor reactive groups on any of the molecules concerned. This may beachieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The term Rx relates to a substituent of the term X and may be absent orselected from the group consisting of hydrogen, C₁₋₈-alkyl,C₃₋₈-cycloalkyl, CH₂—N(R⁵)(R⁵), CH₂—OR⁵, CH₂—SR⁵, CH₂—O—C(═O)R⁵,CH₂—O—C(═S)R⁵; wherein R⁵ is selected from the group consisting ofhydrogen, halogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted C₃₋₈-cycloalkyl, optionallysubstituted C₃₋₈-heterocyclyl, optionally substituted C₁₋₈-alkyl,optionally substituted C₁₋₈-alkylidene, optionally substitutedC₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl and optionallysubstituted C₁₋₈-alkylcarbonyl. In a preferred embodiment, R^(X) isselected from the group consisting of hydrogen, C₁₋₈-alkyl,CH₂—N(R⁵)(R⁵), CH₂—OR⁵, and CH₂—O—C(═O)R⁵. The nature of R^(X) dependson X. It is intended to serve so as to make a prodrug of the molecule,to increase its bioavailability, or to lower the reactivity of the termX, such as in a protective group. In a suitable embodiment, R^(X) is aC₁₋₈-alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl,typically methyl, ethyl or propyl.

As can be derived from the Examples and from the disclosure herein, thecompounds according to Formula I are intended for use as apharmaceutical. Thus, a further aspect of the invention relates to apharmaceutical composition comprising a compound as described herein,together with pharmaceutically acceptable carriers or excipients.Excipients and carriers will depend on, amongst other factors, the routeof administration of the compound.

Compounds of the present invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever specific pharmacological modification of the activityof muscarinic receptors is required.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of Formula I together with apharmaceutically acceptable diluent or excipient. Preferably suchcompositions are in unit dosage forms such as tablets, pills, capsules(including sustained-release or delayed-release formulations), powders,granules, elixirs, tinctures, syrups and emulsions, sterile parenteralsolutions or suspensions, aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories; for oral, parenteral (e.g.,intravenous, intramuscular or subcutaneous), intranasal, sublingual orrectal administration, or for administration by inhalation orinsufflation, and may be formulated in an appropriate manner and inaccordance with accepted practices such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co.,Easton Pa., 1990. Alternatively, the compositions may be insustained-release form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. The present invention alsocontemplates providing suitable topical formulations for administrationto, e.g., eye or skin or mucosa.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents, flavoring agentsand coloring agents can also be incorporated into the mixture. Suitablebinders include, without limitation, starch, gelatin, natural sugarssuch as glucose or beta-lactose, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

For preparing solid compositions such as tablets, the active ingredientis mixed with a suitable pharmaceutical excipient, e.g., such as theones described above, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. By the term “homogeneous” is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. The solid preformulationcomposition may then be subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 50 mg of the activeingredient of the present invention. The tablets or pills of the presentcomposition may be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner core containing the active compoundand an outer layer as a coating surrounding the core. The outer coatingmay be an enteric layer, which serves to resist disintegration in thestomach and permits the inner core to pass intact into the duodenum orto be delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with conventionalmaterials such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the present compositions may be incorporatedfor administration orally or by injection include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil or peanut oil, as well as elixirs and similar pharmaceuticalcarriers. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose, gelatin,methylcellulose or polyvinyl-pyrrolidone. Other dispersing agents, whichmay be employed, include glycerin and the like. For parenteraladministration, sterile suspensions and solutions are desired. Isotonicpreparations, which generally contain suitable preservatives, areemployed when intravenous administration is desired. The compositionscan also be formulated as an ophthalmic solution or suspensionformation, i.e., eye drops, for ocular administration.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses two, three or four times daily. Furthermore, compounds forthe present invention may be administered in intranasal form via topicaluse of suitable intranasal vehicles, or via transdermal routes, usingthose forms of transdermal skin patches well known to persons skilled inthe art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound employed. A physician or veterinarian of ordinary skill canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the disease ordisorder, which is being treated.

The daily dosage of the products may be varied over a wide range from0.01 to 100 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0 or 50.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. A unit dose typically contains from about 0.001mg to about 50 mg of the active ingredient, preferably from about 1 mgto about 10 mg of active ingredient. An effective amount of the drug isordinarily supplied at a dosage level of from about 0.0001 mg/kg toabout 25 mg/kg of body weight per day. Preferably, the range is fromabout 0.001 to 10 mg/kg of body weight per day, and especially fromabout 0.001 mg/kg to 1 mg/kg of body weight per day. The compounds maybe administered on a regimen of 1 to 4 times per day.

Compounds according to the present invention may be used alone atappropriate dosages defined by routine testing in order to obtainoptimal pharmacological effect on a muscarinic receptor, in particularthe muscarinic M₁ or M₄ receptor subtype, while minimizing any potentialtoxic or otherwise unwanted effects. In addition, co-administration orsequential administration of other agents, which improve the effect ofthe compound, may, in some cases, be desirable.

The pharmacological properties and the selectivity of the compounds ofthis invention for specific muscarinic receptor subtypes may bedemonstrated by a number of different assay methods using recombinantreceptor subtypes, preferably of the human receptors if these areavailable, e.g., conventional second messenger or binding assays. Aparticularly convenient functional assay system is the receptorselection and amplification assay disclosed in U.S. Pat. No. 5,707,798describing a method of screening for bioactive compounds by utilizingthe ability of cells transfected with receptor DNA, e.g., coding for thedifferent muscarinic subtypes, to amplify in the presence of a ligand ofthe receptor. Cell amplification is detected as increased levels of amarker also expressed by the cells.

An important aspect of the present invention relates to a method ofincreasing an activity of a cholinergic receptor comprising contactingthe cholinergic receptor or a system containing the cholinergic receptorwith an effective amount of at least one compound of Formula I, asdefined supra. The present investigators have surprisingly found thatthe compounds of Formula I act as cholinergic agonists and, mostremarkably, the compounds of Formula I are selective for the either theM₁ or M₄, or both the M₁ and M₄ muscarinic receptor subtypes.

Furthermore, beyond the remarkable selectivity of the compounds of thepresent invention for the M₁ and M₄ muscarinic receptor subtypes, thepresent investigators have surprisingly found that compounds of FormulaI further act as dopaminergic D₂ antagonists or D₂ inverse agonists.

As was discussed earlier, this combined activity (M₁ and M₄ agonism,dopaminergic D₂ antagonism) is an attractive method of treating an arrayof mental disorders. Consequently, a further important aspect of thepresent invention relates to a method of treating or preventing a mentaldisorder in a mammal, such as a human, comprising the administration ofan effective amount of a compound of Formula I.

Disorders considered to be suitable for treatment by either M₁ and/or M₄agonism, or combined M₁/M₄ agonism and dopaminergic D₂ antagonism areselected from the group consisting of cognitive impairment,forgetfulness, confusion, memory loss, attentional deficits, deficits invisual perception, depression, pain, sleep disorders, psychosis, andincreased intraocular pressure.

Further, suitable disorders considered to be suitable and particularlyattractive may be selected from the group consisting ofneurodegenerative diseases, Alzheimer's disease, Parkinson's disease,schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de laTourette's Syndrome, Down Syndrome, Pick disease, dementia, clinicaldepression, age-related cognitive decline, attention-deficit disorder,sudden infant death syndrome, and glaucoma.

Furthermore the compounds of this invention are useful in the treatmentof mania, bipolar disorder, unipolar disorder, schizoaffective disorder,schizophreniform disorder and anxiety. It should be noted that othernon-schizophrenic causes of psychosis, including drug induced, thoseassociated with dementia and other neurodegenerative disorders (such asHuntington's) are also anticipated to be suitable.

The Tic disorders also include a spectrum of disorders includingTourettes and OCD.

The affective disorder spectrum, including unipolar, bipolar are alsoanticipated to be suitable for treatment using compounds of Formula I.

An important aspect of the invention therefore relates to the use of acompound according or a pharmaceutically acceptable salt thereof, or apharmaceutical composition containing either entity, for the preparationof a medicament for the prophylactic or curative treatment of psychosisor alleviation of symptoms associated with psychosis.

The medicament acts, at least in part, as an M₁ agonist or as M₁ and M₄agonist. The compound according to Formula I may further act as a D₂antagonist. Thus, an important aspect of the invention relates to a useof compounds of Formula I as M₁ and M₄ agonist, as well as D₂antagonists. Illustrative examples of compounds with this combinedactivity are tabulated in Example 1.

Compounds 61KS19, 45NK70, 45NK71, 45NK110, 61KS12 and 61KS13 have highbinding efficacy for the M₁ and M₄ receptor subtypes. Moreover,compounds of Formula I have high selectivity for the M₁ and M₄ receptorsubtypes over M₂, M₃, M₅ receptor subtypes. Further, compounds ofFormula I have D₂ antagonistic activity.

As discussed in Felder et al (J. Med. Chem. 2000), muscarinic receptorsmay be implicated in the control of amyloid precursor processing, inparticular by activation of the M₁ receptor. Thus, a further aspect ofthe present invention relates to a method of modulating or preventingthe progression or formation of amyloid plaques in an individualsusceptible to or affected by Alzheimer's Disease by administering aneffective amount of a compound of Formula I, said effective amountsufficient to modulate amyloid precursor protein processing.

EXAMPLES

Embodiments of the present invention is disclosed in further detail inthe following examples, which are not in any way intended to limit thescope of the invention as claimed.

Example 1 Screening Assay

In the present example, methods for R-SAT and radioligand binding aredescribed. In addition, screening of test compounds in assays usingmuscarinic receptor subtypes M₁ and M₄ and dopamine receptor subtype D₂are described.

Methods

The M₁ and M₄ muscarinic receptor subtypes were cloned substantially asdescribed by Bonner et al., (1987) Science 273 p. 527 and Bonner et al,(1988) Neuron 1, p. 403. R-SAT assays were carried out substantially asdescribed in U.S. Pat. No. 5,707,798 and by Braüner-Osborne, H. B. andBrann, M. R. (1995), Eur. J. Pharmacol. 295:93-102. NIH-3T3 cells(available from the American Type Culture Collection as ATCC CRL 1658)were transfected with plasmid DNA encoding the m1 and m4 receptors andplasmid DNA encoding β-galactosidase. Transfected cells were grown inthe presence of between 1 nM and 40 μM of the test compound for 5 days.On day 5, the cells were lysed using 0.5% nonidet-P and β-galactosidaseexpression was quantified using the chromogenic substrateo-nitrophenyl-β-D-galactoside (ONGP).

Data were normalized relative to the maximum response of the cells tothe muscarinic agonist carbachol, and the following equation was fittedto the data:response=minimum+(maximum−minimum)/(1+([ligand]/EC ₅₀))% Efficacy was defined as (maximum−minimum)/(maximum response of cellsto carbachol). pEC₅₀=−log (EC₅₀). Where data gave a bell-shaped curve,“maximum” was defined as the highest observed response.

The D₂ dopamine receptor subtype was cloned substantially as describedby Stormann, Gdula, Weiner and Brann, 1990 [Mol Pharmacol 37, 1-6]. Cellmembranes expressing the D₂ receptor were prepared by transfecting tSAcells (Chahine, M., Bennet, P. B., George, A. L., Horn, R. (1994)Pfluegers Arch. 427, 136-142) with 10 μg plasmid DNA encoding the humandopamine D₂ receptor and 40 μl Superfect (Qiagen). The cells wereharvested 48 hours and transfection and membranes were prepared byhomogenizing the cells using a Polytron harvester in 20 mM Hepes, 10 mMEDTA, pH 7.4. The homogenate was centrifuged for 30 minutes at 37,000 g.The pellet was homogenized again in 60 ml 20 mM Hepes, 5 mM EDTA. Thehomogenate was centrifuged for 30 minutes at 37,000 g. The supernatantwas discarded. The pellet was homogenized again in 10 ml 20 mM Hepes, 1mM EDTA. The resultant membranes were frozen at −80° C.

The membranes were combined with 150 pM [³H]-Spiperone(Amersham-Pharmacia, 107 Ci/mmol) and ligand concentrations between 1 nMand 10 μM, or haloperidol concentrations between 0.1 nM and 1 μM in 460μl 20 mM Hepes, 1 mM EDTA, 0.1% (w/v) bovine serum albumin. Nonspecificbinding was defined as binding in the presence of 1 μM haloperidol. Themembranes were incubated for 4 hours at 37° C., and then filtered ontoPackard GFB Filterplates using a Packard harvester. The membranes weredried and 50 μl Microscint (Packard) was added to each well. The amountof bound radioligand was quantified using a Packard Topcountscintillation counter.

Data were normalized relative to the maximum inhibition of[³H]-Spiperone binding by 1 μM haloperidol, and the following equationwas fitted to the data:% inhibition=minimum+(maximum−minimum)/(1+([ligand]/[IC ₅₀]))% inhibition was defined as (maximum−minimum)/(maximum response of cellsto haloperidol). pIC₅₀=−log (IC₅₀). NT=not tested.

Results R-SAT M₁ M₄ D₂ % % [³H]Spiperone Compound Efficacy pEC₅₀Efficacy pEC₅₀ pIC₅₀ 61KS-19 115 7.6 141 7.5 6.1 61KS-12 107 7.5 164 7.16.0 45NK-71 71 7.0 49 6.6 6.4 61KS-13 106 7.4 100 7.4 6.4 45NK-70 70 7.340 7.1 6.2 45NK-110 89 7.0 61 5.9 5.5 62KK040d 83 7.6 93 6.4 7.1 61KK6994 7.2 78 6.3 6.7 61KS70-1 96 7.1 112 6.1 6.5 61KS91 106 7.9 88 7.6 6.785LM14 104 7.5 94 5.8 7.1 85LM49B 98 7.6 NT NT 6.3 85LM91-78R 99 7.5 1416.1 7.3 86KK25-a 73 7.0 36 2 6.2 86KKM25-d 84 7.0 63 6.1 6.3 86KK22-K 756.7 56 5.9 6.2 97KK28 71 6.7 NT NT 6.6 85LM12 78 6.9 NT NT 6.4 97KS96-263 7.3 50 2 7.0 79KS97 70 8.2 NT NT 7.0

Example 2 Behavioral Studies

Methods

Animals

Male Non-Swiss Albino mice (Harlan Sprague-Dawley) were housed (4mice/cage) in rooms with temperature and humidity controlled and waterand food (Harlan Teklad) freely available. Mice were kept on a 12-hrlight:dark cycle.

Procedure

Locomotor Activity

Plastic 20×20×30 cm activity cages were equipped with photocell beams(AccuScan Instruments). For spontaneous activity, 61KS19 (1, 3 and 10mg/kg) was administered alone i.p. 30 min before the session. Forhyperactivity experiments, mice were treated with 0.3 mg/kg dizocilpine,3.0 mg/kg d-amphetamine or 3.0 mg/kg scopolamine i.p. 15 min before thesession (15 min after 61KS19). Locomotor data were collected during a 15min session without habituation in a lit room. Each dose combination wastested in a separate group of animals (n=8). Distance traveled (cm) wascalculated and averaged followed by ANOVA and post-hoc Dunnett's t-testcomparisons.

Catalepsy

A custom-built 8-mm rod that is raised 3.5 cm from the lab benchtop wasused. 61KS19 (10 mg/kg) or haloperidol (1 mg/kg) were administered i.p.60 min before the start of the session. The forepaws of each animal isplaced on the rod and the time to step down is measured. If the animalsteps off immediately, another attempt is made until the animal stays onfor more than 10 sec or 10 attempts have been made. A maximum of 2 minis allowed at which time the animal is taken away from the rod andreturned to the homecage. Each dose or dose combination was tested in aseparate group of animals (n=6). Averages and standard errors werecalculated and compared using an ANOVA and post-hoc Dunnett's t-tests.

Example 3 Synthetic Procedures 3.1 General Preparative LC-MS Procedure

Preparative purification was performed on a Waters auto purificationsystem (600 pumps, 2700 sample manager, 996 PDA detector, ZMDmassspectrometer).

The columns used were YMC C18 J'sphere ODS H80. Buffer A was 0.15% TFAin water, buffer B was 0.15% TFA in acetonitrile/water 95/5. The columnswere operated at 17 ml/min. Following an initial hold of 2.5 min at 30%buffer B, compounds were separated using a gradient af 30-100% buffer Bin 8.5 min. A dual column setup with two pumps was used to equilibrateone column, while running on the other.

3.23-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(N-Boc-nortropanone enol triflate) (104KS22)

LDA was generated by adding BuLi (20 mL, 1.68M, 32.6 mmol) to a solutionof diisopropylamine (2.38 g, 32.6 mmol) in dry THF (10 mL) at −78° C.under argon. The mixture was kept at that temperature for 30 minfollowed by the addition of a solution of N-Bocnortropinone (5.27 g,23.4 mmol) in dry THF (20 mL). The mixture was then left stirring for 1h while maintaining the temperature at 78° C. Then a solution of2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (10.08 g,25.7 mmol) in dry THF (20 mL) and the mixture was slowly allowed toreach room temperature overnight and subsequently concentrated andexposed to column chromatography (SiO₂; EtOAc/heptane 1:6,R_(f)(product)=0.31) to give the title compound (104KS22) (6.68 g, 80%)which on prolonged standing crystallised into a white solid. ¹H NMR(CDCl₃) δ 1.43 (s, 9H, Boc-CH ₃), 1.72 (m, 1H), 1.93-2.03 (m, 2H), 2.07(d, J=16.6 Hz, 1H), 2.23 (broad m, 1H), 3.05 (broad s, 1H), 4.42 (broadm, 2H, H1+H5), 6.10 (broad s, 1H, H2). ¹³C NMR (CDCl₃) δ 28.4 (Boc CH₃),30.1 and 29.2 (rotameric), 34.7 and 34.9 (rotameric), 36.5 and 37.1(rotameric), 51.9, (broad s), 80.5 ((CH₃)₃ C—), 118.7 (—CF₃, q, J=300Hz), 124.0 (broad s, C2), 148.0 (broad s, C3), 153.9 (Boc C═O).

3.3 General Procedure 1 (GP1)

To a mixture of3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.107 g, 0.3 mmol, 1.0 equiv), CuI (0.011 g, 0.05 moles, 0.20equiv), dimethylethylamine (0.219 g, 3.0 mmol, 10 equiv) and the alkyne(2.0 equiv) in dry THF (3 mL) was added (PPh₃)₄Pd (0.10 equiv) at roomtemperature under argon. The mixture was shaken for 2 h followed byfiltration and concentration. The residual syrup was taken up in DCM (2mL) followed by careful addition of TFA (0.5 mL). The mixture was shakenfor 10 min before it was concentrated, basified with NaOH (2M, 3 mL),extracted (EtOAc), concentrated and put on an ionexchange column (VarianBondElut®-SCX, H⁺). Elution with 2.5% NH₄OH in MeOH and concentrationgave the desired product.

3.4 3-Pent-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-5)

3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.107 g, 0.3 mmol) and Pent-1-yne (0.041 g, 0.6 mmol) werereacted according to GP1 to give the title compound (79KS36-5) (0.033 g,62%). HPLC-MS (ammonium acetate): [M+H]⁺=176.23

3.5 3-Hex-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-6)

3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.107 g, 0.3 mmol) and Hex-1-yne (0.049 g, 0.6 mmol) werereacted according to GP1 to give the title compound (79KS36-6) (0.049 g,86%). HPLC-MS (ammonium acetate): [M+H]⁺=190.26

3.6 3-Hept-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-7)

3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.107 g, 0.3 mmol) and Hept-1-yne (0.058 g, 0.6 mmol) werereacted according to GP1 to give the title compound (79KS36-7) (0.051 g,84%). HPLC-MS (ammonium acetate): [M+H]⁺=204.28

3.7 4-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-but-3-yn-1-ol (79KS36-2)

3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.107 g, 0.3 mmol) and But-3-yn-1-ol (0.042 g, 0.6 mmol) werereacted according to GP1 to give the title compound (79KS36-2) (0.018 g,34%). HPLC-MS (ammonium acetate): [M+H]⁺=178.21

3.8 5-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-pent-4-yn-1-ol (79KS36-3)

3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.107 g, 0.3 mmol) and Pent-3-yn-1-ol (0.050 g, 0.6 mmol)were reacted according to GP1 to give the title compound (79KS36-3)(0.045 g, 79%). HPLC-MS (ammonium acetate): [M+H]⁺=192.23

3.9 General Method 2 (GP2)

To a slurry of CuI (2.0 equiv) in dry THF (5 mL) was added R-M (R=alkyl,M=Li or MgX) (4.0 equiv) at −25° C. and stirred at that temperature for30 min before adding a solution of3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (1.0 equiv) in dry THF (5 mL). The reaction mixture was keptstirring at −25° C. for 2 h before the cooling was removed. The reactionwas then quenched by firstly addition of water (20 mL) and secondlyaddition of a saturated aqeuous solution of NH₄Cl (20 mL) beforeextraction with DCM. The combined organic phase was washed with asaturated aqeuous solution of NH₄Cl, dried (Na₂SO₄), filtered andconcentrated in vacuo to give the crude product. This was then purifiedby column chromatography (SiO₂; EtOAc/heptane 1:10 which gave thedesired products

3.10 8-tertButyloxycarbonyl-3-propyl-8-aza-bicyclo[3.2.1]oct-2-ene(79KS74)

CuI (0.234 g, 1.23 mmol), PrMgBr (1.3 mL, 2.0M, 2.46 mmol)3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.220 g, 0.616 mmol) were reacted according to GP2 to givethe title compound (79KS74) (0.083 g, 54%). ¹H NMR (CDCl₃) δ 0.84 (t,3H, J=7.1 Hz, —CH₂CH₂CH ₃), 1.36 (sixt, 2H, J=7.1 Hz, —CH₂CH ₂CH₃), 1.43(s, 9H, Boc-CH₃), 1.56 (dt, 1H, J=7.0 Hz, 13.2 Hz), 1.64 (d, 1H, J=17.0Hz), 1.76-1.96 (m, 4H), 2.11 (m, 1H), 2.67 (d, 1H, J=17.0 Hz), 4.18-4.34(m, 2H), 5.68 (d, 1H, J=4.8 Hz, H2); ³C NMR (CDCl₃) δ 13.7 (—CH₂CH₂CH₃), 20.7 (—CH₂ CH₂CH₃), 28.6 (Boc-CH₃), 30.0, 34.9, 37.4, 38.5(—CH₂CH₂CH₃), 52.3, 53.3, 79.2 (—C(CH₃)₃), 126.6, 135.4 (C2, C3), 154.4(C═O).

3.11 8-tertButyloxycarbonyl-3-butyl-8-aza-bicyclo[3.2.1]oct-2-ene(79KS61)

CuI (0.289 g, 1.52 mmol), BuLi (1.9 mL, 1.6 M, 3.03 mmol)3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.271 g, 0.758 mmol) were reacted according to GP2 to givethe title compound (79KS61) (0.104 g, 52%). ¹H NMR (CDCl₃) δ 0.82 (t,3H, J=7.2 Hz, —CH₂CH₂CH₂CH ₃), 1.14-1.34 (m, 4H), 1.40 (s, 9H, Boc-CH₃), 1.53 (dt, 1H, J=7.6 Hz, 13.3 Hz), 1.61 (d, 1H, J=17.1 Hz), 1.72-1.92(m, 4H), 2.07 (m, 1H), 2.64 (d, 1H, J=17.1 Hz), 4.14 (m, 2H), 5.64 (d,1H, J=4.6H, H2); ¹³C NMR (CDCl₃) δ 14.1 (—CH₂CH₂CH₂ CH₃), 22.3 (—CH₂CH₂CH₂CH₃), 28.6 (Boc-CH₃), 29.7 (—CH₂ CH₂CH₂CH₃), 30.0, 34.8, 36.1(—CH₂CH₂CH₂CH₃), 37.5, 52.3, 53.3, 79.1 (—C(CH₃)₃), 126.4, 135.6 (C2,C3), 154.4 (C═O).

3.12 8-tertButyloxycarbonyl-3-pentyl-8-aza-bicyclo[3.2.1]oct-2-ene(79KS94)

CuI (0.712 g, 3.74 mmol), pentyl-MgBr (3.8 mL, 2.0 M, 7.48 mmol)3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.669 g, 1.87 mmol) were reacted according to GP2 to give thetitle compound (79KS94) (0.238 g, 46%). ¹H NMR (CDCl₃) δ 0.87 (t, 3H,J=7.2 Hz, —CH₂CH₂CH₂CH₂CH ₃), 1.15-1.38 (m, 6H), 1.44 (s, 9H, Boc-CH₃),1.57 (dt, 1H, J=8.0 Hz, J=12.0 Hz), 1.65 (d, 1H, J=17.1 Hz), 1.76-1.96(m, 4H), 2.06-2.17 (m, 1H), 2.68 (d, 1H, J=17.1 Hz), 4.22-4.32 (m, 2H),5.68 (d, 1H, J=5.0 Hz, H2); ¹³C NMR (CDCl₃) δ 14.2 (—CH₂CH₂CH₂CH₂ CH₃),22.7 (—CH₂CH₂CH₂ CH₂CH₃), 27.2 (—CH₂CH₂ CH₂CH₂CH₃), 28.6 (Boc-CH₃),30.0, 31.5 (—CH₂ CH₂CH₂CH₂CH₃), 34.9, 36.4 (—CH₂CH₂CH₂CH₂CH₃), 37.5,52.3, 53.3, 79.2 (—C(CH₃)₃), 126.4, 135.7 (C2, C3), 154.4 (C═O).

3.13 8-tertButyloxycarbonyl-3-hexyl-8-aza-bicyclo[3.2.1]oct-2-ene(79KS79)

CuI (0.234 g, 1.23 mmol), hexyl-MgBr (1.23 mL, 2.0 M, 7.48 mmol)3-Trifluorosulfonyl-8-tertButyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene(104KS22) (0.220 g, 0.616 mmol) were reacted according to GP2 to givethe title compound (79KS79) (0.073 g, 40%). ¹H NMR (CDCl₃) δ 0.85 (t,3H, J=6.7 Hz, —CH₂CH₂CH₂CH₂CH₂CH ₃), 1.14-1.38 (m, 8H), 1.42 (s, 9H,Boc-CH₃), 1.50-1.60 (m, 1H), 1.63 (d, 1H, J=16.8 Hz), 1.74-1.94 (m, 4H),2.03-2.17 (m, 1H), 2.65 (br s, 1H), 4.25 (br s, 2H), 5.65 (br s, 1H,H2); ¹³C NMR (CDCl₃) δ 14.2 (—CH₂CH₂CH₂CH₂CH₂ CH₃), 22.8 (—CH₂CH₂CH₂CH₂CH₂CH₃), 27.5 (—CH₂CH₂CH₂ CH₂CH₂CH₃), 28.6 (Boc-CH₃), 28.9 (—CH₂CH₂CH₂CH₂CH₂CH₃), 30.1, 31.9 (—CH₂ CH₂CH₂CH₂CH₂CH₃), 34.8, 36.4(—CH₂CH₂CH₂CH₂CH₂CH₃), 37.6, 52.3, 53.2, 79.2 (—C(CH₃)₃), 126.3, 135.9(C2, C3), 154.4 (C═O).

3.14 General Procedure 3 (GP3)

The alkene (1.0 equiv) was dissolved in MeOH (3 mL) and Pd(10%)/C (tipof a spatula) was added. H₂ (1 atm., balloon) was applied understirring. The reaction mixture was left stirring for 2.5 h before it wasfiltered through a pad of celite and concentrated in vacuo to give thedesired products which was pure enough for further reaction.

3.15 8-tertButyloxycarbonyl-3-propyl-8-aza-bicyclo[3.2.1]octane (79KS75)

8-tertButyloxycarbonyl-3-propyl-8-aza-bicyclo[3.2.1]oct-2-ene (79KS74)(0.039 g, 0.155 mmol) was reacted according to GP3 to give the titlecompound (79KS75) (0.030 g, 76%). ¹H NMR (CDCl₃) δ 0.86 (t, 3H, J=7.5Hz, —CH₂CH₂CH ₃), 1.08-1.17 (m, 2H), 1.20-1.36 (m, 4H), 1.44 (s, 9H,Boc-CH ₃), 1.52 (m, 2H, J=13.8 Hz), 1.56-1.64 (m, 2H), 1.70-1.82 (m,1H), 1.86-1.94 (m, 2H), 4.05 (br s, 2H, H2); ¹³C NMR (CDCl₃) δ 14.4(—CH₂CH₂ CH₃), 20.0 (—CH₂ CH₂CH₃), 28.2, 28.4, 28.7 (Boc-CH₃), 38.0,39.5, 53.8, 79.0 (—C(CH₃)₃), 153.7 (C═O).

3.16 8-tertButyloxycarbonyl-3-butyl-8-aza-bicyclo[3.2.1]octane (79KS92)

8-tertButyloxycarbonyl-3-butyl-8-aza-bicyclo[3.2.1]oct-2-ene (79KS61)(0.047 g, 0.177 mmol) was reacted according to GP3 to give the titlecompound (79KS92) (0.045 g, 95%). ¹H NMR (CDCl₃) δ 0.86 (t, 3H, J=6.6Hz, —CH₂CH₂CH₂CH ₃), 1.10-1.40 (m, 8H), 1.45 (s, 9H, Boc-CH ₃),1.47-1.56 (m, 2H, J=13.2), 1.56-1.64 (m, 2H), 1.68-1.82 (m, 1H),1.85-1.98 (m, 2H), 4.18 (m, 2H); ¹³C NMR (CDCl₃) δ 14.5 (—CH₂CH₂CH₂CH₃), 23.3 (—CH₂CH₂ CH₂CH₃), 28.4, 28.7 (Boc-CH₃), 29.0, 29.4 (—CH₂CH₂CH₂CH₃), 37.1 (—CH₂CH₂CH₂CH₃), 37.9, 38.7, 53.6, 54.4, 79.2(—C(CH₃)₃), 153.9 (C═O).

3.17 3-Pentyl-8-aza-bicyclo[3.2.1]octane (79KS95)

8-tert-Butyloxycarbonyl-3-pentyl-8-aza-bicyclo[3.2.1]oct-2-ene (79KS94)(0.199 g, 0.712 mmol) was dissolved in CHCl₃ (3 mL) and TFA (1 mL) wasadded and the mixture was left stirring for 30 min. The mixture was thenbasified (2M NaOH), extracted (CHCl₃), dried (Na₂SO₄), filtered andconcentrated. The resultant syrup was reacted according to GP3 to givethe title compound (79KS95) (0.126 g, 98%). ¹H NMR (CDCl₃) δ 0.84 (t,3H, J=7.1 Hz, —CH₂CH₂CH₂CH₂CH ₃), 1.13-1.46 (m, 8H), 1.65-1.77 (m, 3H),1.88-2.00 (m, 2H), 2.16 (ddd, 2H, J=5.3 Hz, 8.3 Hz, 13.5 Hz), 3.62 (brs, 2H), 5.80 (br s, 1H, NH); ¹³C NMR (CDCl₃) δ 14.2 (—CH₂CH₂CH₂CH₂ CH₃),22.8 (—CH₂CH₂CH₂ CH₂CH₃), 28.0, 28.3, 28.7, 28.8, 32.0, 35.1, 37.6, 54.0(C2+C5).

3.18 8-tert-Butyloxycarbonyl-3-hexyl-8-aza-bicyclo[3.2.1]octane (79KS81)

8-tert-Butyloxycarbonyl-3-hexyl-8-aza-bicyclo[3.2.1]oct-2-ene (79KS79)(0.035 g, 0.119 mmol) was reacted according to GP3 to give the titlecompound (79KS81) (0.027 g, 77%). ¹H NMR (CDCl₃) δ 0.85 (m, 3H,—CH₂CH₂CH₂CH₂CH₂CH ₃), 1.10-1.40 (m, 11H), 1.45 (s, 9H, Boc-CH ₃),1.51-1.55 (m, 2H), 1.58-1.63 (m, 2H), 1.69-1.82 (m, 1H), 1.85-1.95 (m,2H), 4.05-4.25 (m, 2H); ¹³C NMR (CDCl₃) δ 14.2 (—CH₂CH₂CH₂CH₂CH₂ CH₃),22.8 (—CH₂CH₂CH₂CH₂ CH₂CH₃), 26.9, 28.2, 28.5, 28.8 (Boc-CH₃), 29.7,32.1, 37.2, 37.7, 38.5, 53.5, 54.2, 79.0 (—C(CH₃)₃), 153.7 (C═O).

3.19 General Method 4 (GP4)

NaH (55% in mineral oil, 5 equiv) was washed with heptane (2-10 mL) andcovered with dry THF (5-20 mL). This was then stirred vigorouslyfollowed by the addition of a solution of1-tert-Butyloxycarbonylpiperidin-4-ol (1.0 equiv) in dry THF (5-20 mL)was carefully added. The stirring was continued for 30 min before addingan alkylhalide (1.2 equiv) in small portions. The stirring was continuedfor another 18 h before quenching the reaction with water (10-100 mL).Then the mixture was extracted (EtOAc) followed by drying (Na₂SO₄) ofthe combined organic phase. Filtration and concentration in vacuo gave asyrup which was purified by column chromatography (SiO₂; EtOAc/heptane1:6 which gave the desired products.

3.20 1-tert-Butyloxycarbonyl-4-(prop-2-ene-1-oxy)-piperidine (104KS20)

NaH (16.4 g, 55% in mineral oil, 375 mmol),1-tert-Butyloxycarbonylpiperidin-4-ol (15.1 g, 75.0 mmol) and allylbromide (10.9 g, 90.0 mmol) were reacted according to GP4 to give thetitle compound (104KS20) (14.8 g, 82%). ¹H NMR (CDCl₃) δ 1.45 (s, 9H,Boc-CH ₃), 1.45-1.60 (m, 2H), 1.76-1.86 (m, 2H), 3.08 (ddd, 2H, J=4.1Hz, 9.5 Hz, 13.4 Hz), 3.45-3.54 (m, 1H), 3.70-3.84 (m, 2H), 3.98-4.07(m, 2H), 5.16 (m, 1H, J=10.8 Hz, —OCH₂CH═CH _(c)H_(t)), 5.27 (m, 1H,J=16.7 Hz, —OCH₂CH═CH_(c) H _(t)), 5.85-5.98 (m, 1H,—OCH₂CH═CH_(c)H_(t)); ¹³C NMR (CDCl₃) δ 28.7 (Boc-CH₃), 31.3, 41.6,69.1, 74.2, 79.6 (—C(CH₃)₃), 116.8 (—OCH₂CH═CH₂), 135.4 (—OCH₂ CH═CH₂),155.1 (C═O).

3.21 1-tertButyloxycarbonyl-4-(cyclobutylmethoxy)-piperidine (61KS51)

NaH (0.398 g, 55% in mineral oil, 9.94 mmol),1-tertButyloxycarbonylpiperidin-4-ol (2.00 g, 9.94 mmol) and(Bromomethyl)cyclobutane (1.35 g, 9.04 mmol) were reacted according toGP4 to give the title compound (61KS51) (0.212 g, 9%). ¹H NMR (CDCl₃) δ1.40-1.58 (m, 11H), 1.68-1.96 (m, 6H), 2.00-2.15 (m, 2H), 2.55 (m, 1H),3.10 (ddd, 2H, J=3.0 Hz, 8.3 Hz, 13.3 Hz), 3.35-3.50 (m, 3H), 3.70-3.83(m, 2H); ¹³C NMR (CDCl₃) δ 18.8, 25.3, 28.7 (Boc-CH₃), 31.4, 35.6, 41.5,72.9, 74.7, 79.6 (—C(CH₃)₃), 155.1 (C═O).

3.22 1-tertButyloxycarbonyl-4-hydroxymethyl-piperidine (61KS81)

4-(Hydroxymethyl)piperidine (0.953 g, 8.27 mmol) was dissolved indioxane/water (1:1, 50 mL) followed by the addition of Boc₂O (2.17 g,9.92 mmol) and NaHCO₃ (8.77 g, 82.7 mmol). The mixture was stirred atroom temperature for 24 h before extraction with DCM was performed. Thecombined organic phase was washed consecutively with citric acid (5%sol.) and aqueous NaHCO₃ followed by drying (Na₂SO₄), filtration andevaporation of the solvent to give the title compound (61KS81) (1.75 g,98%). ¹H NMR (CDCl₃) δ 1.15 (dq, 2H, J=4.8 Hz, 12.4 Hz), 1.45 (s, 9H,Boc-CH ₃), 1.58-1.75 (m, 3H), 2.70 (t, 2H, J=12.0 Hz), 3.49 (d, 2H,J=6.0 Hz, —CH ₂OH), 4.00-4.23 (m, 2H); ¹³C NMR (CDCl₃) δ 28.7 (Boc-CH₃),30.3, 39.0, 43.7, 67.3, 67.8, 79.5 (—C(CH₃)₃), 155.1 (C═O).

3.23 1-tertButyloxycarbonyl-4-methoxymethyl-piperidine (61KS83)

MeI (0.094 g, 0.659 mmol, 1.1 eq),1-tertButyloxycarbonyl-4-hydroxymethyl-piperidine (61KS81) (0.129 g,0.599 mmol, 1.0 eq) and NaH (0.029 g, 55% in mineral oil, 0.719 mmol,1.2 eq) were reacted according to GP4 to give the title compound(61KS83) (0.076 g, 56%). ¹H NMR (CDCl₃) δ 1.10 (dq, 2H, J=4.7 Hz, 12.2Hz), 1.40 (s, 9H, Boc-CH ₃), 1.60-1.75 (m, 3H), 2.63 (t, 2H, J=12.7 Hz),3.18 (d, 2H, J=6.0 Hz, —CH ₂OCH₃), 3.29 (s, 3H, —CH₂OCH ₃), 3.94-4.15(m, 2H); ¹³C NMR (CDCl₃) δ 28.6 (Boc-CH₃), 29.2, 36.7, 43.9, 59.0, 77.8,79.4 (—C(CH₃)₃), 155.0 (C═O).

3.24 1-tertButyloxycarbonyl-4-ethoxymethyl-piperidine (61KS90)

1-tertButyloxycarbonyl-4-hydroxymethyl-piperidine (61KS81) (0.100 g,0.464 mmol), NaH (0.093 g, 55% in mineral oil, 2.32 mmol) and EtOMs(0.345 g, 2.78 mmol) were reacted according to GP4 to give the titlecompound (61KS90) (0.071 g, 63%). ¹H NMR (CDCl₃) δ 1.08 (dq, 2H, J=4.1Hz, 12.9 Hz), 1.14 (t, 3H, 6.8 Hz, —CH₂OCH₂CH ₃), 1.42 (s, 9H, Boc-CH₃), 1.63-1.75 (m, 3H), 2.65 (t, 2H, 12.8 Hz), 3.21 (d, 2H, J=6.1 Hz, —CH₂OCH₂CH₃), 3.42 (q, 2H, J=6.8 Hz, —CH₂OCH ₂CH₃), 3.96-4.14 (m, 2H); ¹³CNMR (CDCl₃) δ 15.3 (—CH₂OCH₂ CH₃), 28.6 (Boc-CH₃), 29.3, 36.8, 66.6,75.6, 79.4 (—C(CH₃)₃), 155.1 (C═O).

3.25 1-tertButyloxycarbonyl-4-hydroxyethyl-piperidine (61KS82)

4-Piperidineethanol (1.05 g, 8.13 mmol) was dissolved in dioxane/water(1:1, 50 mL) followed by the addition of Boc₂O (2.13 g, 9.76 mmol) andNaHCO₃ (8.62 g, 81.3 mmol). The mixture was stirred at room temperaturefor 24 h before extraction with DCM was performed. The combined organicphase was washed consecutively with citric acid (5% sol.) and aqueousNaHCO₃ followed by drying (Na₂SO₄), filtration and evaporation of thesolvent to give the title compound (61KS82) (1.77 g, 95%). ¹H NMR(CDCl₃) δ 1.12 (dq, 2H, J=4.6 Hz, 11.8 Hz), 1.35-1.55 (m, 14H), 2.70 (t,2H, J=12.8 Hz), 3.70 (t, 2H, J=6.3 Hz, —CH₂CH ₂OH), 3.95-4.20 (m, 2H);¹³C NMR (CDCl₃) δ 28.7 (Boc-CH₃), 32.8, 39.5, 44.2, 60.5, 67.3, 79.4(—C(CH₃)₃), 155.1 (C═O).

3.26 1-tertButyloxycarbonyl-4-(2-methoxyethyl)-piperidine (61KS86)

MeI (3.72 g, 2.62 mmol),1-tertButyloxycarbonyl-4-hydroxyethyl-piperidine (61KS82) (1.00 g, 4.36mmol) and NaH (0.872 g, 55% in mineral oil, 21.8 mmol) were reactedaccording to GP4 to give the title compound (61KS86) (0.447 g, 42%). ¹HNMR (CDCl₃) δ 1.10 (dq, 2H, J=4.2 Hz, 12.2 Hz), 1.38-1.70 (m, 14H), 2.68(t, 2H, 12.6 Hz), 3.32 (s, 3H, —CH₂CH₂OCH ₃), 3.40 (t, 2H, J=6.0 Hz,—CH₂CH ₂OCH₃), 4.00-4.15 (m, 2H); ¹³C NMR (CDCl₃) δ 28.7 (Boc-CH₃),32.4, 33.1, 36.4, 44.1, 58.8 (—CH₂CH₂OCH₃), 70.4 (—CH₂ CH₂OCH₃), 79.4(—C(CH₃)₃), 155.1 (C═O).

3.27 General Procedure 5 (GP5)

The alkene (1.0 equiv) was dissolved in MeOH (10-50 mL) and ammoniumformate (10 equiv) was added. The reaction flask was then flushed withargon before adding Pd(10%)/C (30-700 mg). The reaction mixture wasstirred for 4 h before the catalyst was filtered off using celite asfilter aid. After concentration the product was taken up in DCM (5-30mL) and filtered through cotton wool and concentrated to give thedesired products.

3.28 1-tertButyloxycarbonyl-4-propoxy-piperidine (104KS21)

1-tertButyloxycarbonyl-4-(prop-2-ene-1-oxy)-piperidine (104KS20) (7.60g, 31.5 mmol), ammonium formate (20 g, 315 mmol) and Pd(10%)/C (0.500 g)were reacted according to GP5 to give the title compound (104KS21) (5.61g, 73%). ¹H NMR (CDCl₃) δ 0.90 (m, 3H), 1.42 (s, 9H, Boc-CH ₃),1.35-1.60 (m, 4H), 1.70-1.85 (m, 2H), 3.00-3.15 (m, 2H), 3.30-3.44 (m,3H), 3.65-3.70 (2H); ¹³C NMR (CDCl₃) δ 10.8 (—OCH₂CH₂ CH₃), 23.5 (—OCH₂CH₂CH₃), 28.6 (Boc-CH₃), 31.3, 41.5 (C2 and C3), 69.9, 74.5 (C4 and—OCH₂CH₂CH₃), 79.5 (—C(CH₃)₃), 155.0 (C═O).

3.29 1-tertButyloxycarbonyl-4-(isobutoxy)-piperidine (61KS66)

3-Bromo-2-methylpropen (0.578 g, 4.28 mmol), NaH (0.189 g, 55% inmineral oil, 4.71 mmol), 1-tertButyloxycarbonylpiperidin-4-ol (0.948 g,4.71 mmol), Pd(10%)/C (0.700 g), ammonium formate (1.84 g, 2.91 mmol)were reacted according to GP4 and GP5 to give the title compound(61KS66) (0.740 g, 67% over 2 steps). ¹H NMR (CDCl₃) δ 0.90 (d, 6H,J=6.7 Hz, —OCH₂CH(CH ₃)₂), 1.44 (s, 9H, Boc-CH ₃), 1.46-1.56 (m, 2H),1.73-1.87 (m, 3H), 3.15 (ddd, 2H, J=3.2 Hz, 8.5 Hz, 13.1 Hz), 3.19 (d,2H, J=6.7 Hz, —OCH ₂CH(CH₃)₂), 3.39 (tt, 1H, J=3.2 Hz, 8.0 Hz),3.65-3.76 (m, 2H); ¹³C NMR (CDCl₃) δ 19.6, 28.6, 28.7 (Boc-CH₃), 31.2,41.4, 74.6 (C4), 75.2 (—OCH₂CH(CH₃)₂), 79.5 (—C(CH₃)₃), 155.1 (C═O).

3.30 4-Propyloxypiperidine (79KS66)

To solution of the Boc-protected piperidine1-t-butyloxycarbonyl-4-propyloxypiperidine (104KS21) (12.6 g, 51.8 mmol)in DCM (30 mL) was carefully added TFA (25 mL) under stirring. Themixture was left stirring for 18 h and concentrated in vacuo. To theremaining syrup was added 2M NaOH (20 mL) and this mixture was extractedwith DCM. The combined organic phase was dried (Na₂SO₄), filtered andconcentrated to give the title compound (79KS66) (7.4 g, quant.) as ayellow oil. The material was used for the next reaction step withoutfurther purification. ¹H NMR (CDCl₃): δ 0.89 (t, 3H, J=7.4 Hz,—OCH₂CH₂CH ₃), 1.40-1.50 (m, 2H), 1.55 (sixt, 2H, J=7.4 Hz, —OCH₂CH₂CH₃), 1.84-1.94 (m, 2H), 2.64 (ddd, 2H, J=3.0 Hz, 9.8 Hz, 12.7 Hz),3.35 (dt, 2H, J=1.5 Hz, 12.7 Hz), 3.21 (br s, 1H, NH), 3.30-3.37 (m, 1H,H4), 3.35 (td, 2H, J=1.2 Hz, 7.4 Hz, —OCH ₂CH₂CH₃); ¹³C NMR (CDCl₃): δ10.8 (—OCH₂CH₂ CH₃), 23.5 (—OCH₂ CH₂CH₃), 32.5, 44.1 (C2 and C3), 69.7(—OCH₂CH₂CH₃), 74.8 (C4).

3.31 4-Cyclohexylmethyl-piperidine (56NK128)

Platinium dioxide (200 mg) was added to 4-benzylpiperidine (1.75 g, 10mmol) in EtOH (20 ml) and HCl in dioxan (20 ml, 4 M). The flask wasevacuated, flooded with hydrogen and this procedure was repeated twice.The reaction was stirred vigorously at r.t. for 72 h then platiniumoxide (200 mg) was added and the reaction was stirred at r.t. for 18 h.The reaction mixture was filtered through Celite eluting with EtOAc andthe solute concentrated in vacuo. Ether (50 ml) was added and thereaction concentrated in vacuo. Water (50 ml) and ether (50 ml) wereadded then sodium hydroxide (2 M) was added until pH 12. The phases wereseparated and the aqueous phase was extracted with ether (2×50 ml). Theorganic phases were combined, washed with brine (20 ml), dried (K₂CO₃),filtered and carefully concentrated in vacuo to give the crude titlecompound (56NK128) as a pale yellow oil (1.42 g, 78%). ¹H NMR (CDCl₃) δ3.04 (m, 2H), 2.56 (m, 2H), 1.72-1.55 (m, 9H), 1.45 (m, 1H), 1.32 (m,1H), 1.18 (m, 2H), 1.05 (m, 4H), 0.83 (m, 2H); HPLC-MS (ammoniumacetate) [M+H]⁺=182.3 (calc. 182.2).

3.32 4-(2-Ethoxyethyl)piperidine (56NK129)

4-(2-Ethoxyethyl)pyridine (0.151 g, 1.0 mmol) was dissolved in EtOH (4ml) and acetic acid (0.5 ml) and the flask was evacuated, flooded withhydrogen and this procedure was repeated twice. Platinium oxide (0.040g) was added and the reaction was stirred vigorously at r.t. for 18 h.The reaction mixture was filtered through Celite eluting with EtOAc andthe solute concentrated in vacuo. Ether (20 ml) was added and thereaction concentrated in vacuo. Sodium hydroxide (2 ml, 2 M) was addedand the product was extracted into ether (2×20 ml). The organic phaseswere dried (K₂CO₃), filtered and carefully concentrated in vacuo to givethe crude title compound (56NK129) as a yellow oil (0.154 g, 98%). ¹HNMR (CDCl₃) δ 3.45 (m, 4H), 3.03 (m, 2H), 2.58 (m, 2H), 1.76 (br. S,1H), 1.66 (m, 2H), 1.51 (m, 3H), 1.18 (t, J=7.5 Hz, 3H), 1.11 (m, 2H);HPLC-MS (ammonium acetate) [M+H]⁺=158.2 (calc. 158.2).

3.33 4-Cyclohexylpiperidine (75NK45)

Platinium dioxide (0.200 g) was added to 4-phenylpiperidine (1.55 g, 10mmol) in EtOH (40 ml) and HCl in dioxan (5 ml, 4 M). The flask wasevacuated, flooded with hydrogen and this procedure was repeated twice.The reaction was stirred vigorously at r.t. for 72 h then filteredthrough Celite eluting with EtOAc and the solute was concentrated invacuo to give a white solid. Water (30 ml) was added followed by sodiumhydroxide (20 ml, 2 M) and the product was extracted into EtOAc (3×50ml). The organic phase was washed with brine (20 ml), dried (K₂CO₃),filtered and carefully concentrated in vacuo to give the crude titlecompound (75NK45) as a pale yellow oil (1.38 g, 82%). ¹H NMR (CDCl₃) δ3.07 (m, 2H), 2.58 (m, 2H), 1.93 (br. s, 1H), 1.71 (m, 4H), 1.64 (m,4H), 1.16 (m, 6H), 0.95 (m, 2H); HPLC-MS (ammonium acetate) [M+H]⁺=168.2(calc. 168.3).

3.35 General Procedure 6 (GP6)

A 4 ml vial was charged with Aniline (1 equiv) and carbonyldiimidazole(1.3 equiv) in DMF (1 ml) and shaken at 60° for 4 h. The reaction wascooled to r.t. and 4 M HCl added (1 ml). The product was extracted intoethyl acetate (2×1 ml) and the combined org. layer filtered through aWHATMAM FT 5.0 μm PTFE column. The solute was concentrated in vacuo andused without further purification.

3.36 4-Methyl-3H-benzooxazol-2-one (86KK20a)

2-Hydroxy-6-methylanilin (0.154 g, 1.25 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20a).

3.37 5,7-Dimethyl-3H-benzooxazol-2-one (86KK20b)

2-Hydroxy-3,5-dimethylanilin (0.66 g, 1.21 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20b).

3.38 6-Methyl-3H-benzooxazol-2-one (86KK20c)

2-Hydroxy-4-methylanilin (0.145 g, 1.17 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20d).

3.39 5-Methyl-3H-benzooxazol-2-one (86KK20d)

2-Hydroxy-5-methylanilin (0.147 g, 1.19 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20d).

3.40 5-t-Butyl-3H-benzooxazol-2-one (86KK20e)

2-Hydroxy-5-t-butylanilin (0.203 g, 1.23 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20e).

3.41 6-Chloro-3H-benzooxazol-2-one (86KK20f)

4-Chloro-2-hydroxyanilin (0.179 g, 1.25 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20f).

3.42 5-Methoxy-3H-benzooxazol-2-one (86KK20i)

2-Hydroxy-5-methoxyanilin (0.175 g, 1.26 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20i).

3.43 6-Fluoro-3H-benzooxazol-2-one (86KK20j)

4-Fluoro-2-hydroxyanilin (0.154 g, 1.21 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20j).

3.44 5-Fluoro-3H-benzooxazol-2-one (86KK20k)

5-Fluoro-2-hydroxyanilin (0.117 g, 0.92 mmol) and carbonyldiimidazole(0.250 g, 1.54 mmol) were reacted according to GP6 to give the crudetitle compound (86KK20k).

3.45 General Procedure 7 (GP7)

A 4 ml vial was charged with hydroxybenzoic acid (1 equiv) andcarbonyldiimidazole (1.2 equiv) in THF (1 ml) and shaken at 60° for 20h. The reaction was cooled to r.t., 4 M HCl added (1 ml), and theproduct was extracted into EtOAc (2×1 ml). The combined org. layer wasdried over Na₂SO₄ and concentrated in vacuo before being purified byflash column chromatography (CC) give of the product.

3.46 5,7-Dichloro-6-ethyl-3H-benzooxazol-2-one (97KK10)

3,5-Dichloro-4-ethyl-2-hydroxybenzoic acid (0.288 g, 1.40 mmol) andcarbonyldiimidazole (0.275 g, 1.70 mmol) were reacted according to GP7.Purified by flash CC (SiO₂; DCM/MeOH 40:1) to give the title compound(97KK10) (0.269 g, 83%). ¹H-NMR (MeOH) δ 1.14 (t, J=7.4 Hz, CH₃), 2.92(q, J=7.4 Hz, CH₂), 7.04 (s, 1H); ¹³C (MeOH) δ 13.2, 24.9, 110.4, 116.4,130.2, 130.9, 134.4, 141.2, 155.8.

3.47 7-Fluoro-3H-benzooxazol-2-one (97KK09a)

3-Fluoro-2-hydroxybenzoic acid (0.265 g, 2.08 mmol) andcarbonyldiimidazole (0.352 g, 2.17 mmol) were reacted according to GP7.Purified by flash CC (SiO₂; DCM/MeOH 20:1) to give the title compound(97KK09a) (0.189 g, 59%). ¹H-NMR (CDCl₃) δ 6.90-6.85 (m, 1H), 7.38-7.33(m, 1H), 7.86-7.83 (m, 1H), 10.38 (br. s, 1H).

3.48 5-Bromo-7-fluoro-3H-benzooxazol-2-one (97KK09b)

5-Bromo-3-fluoro-2-hydroxybenzoic acid (0.080 g, 0.39 mmol) andcarbonyldiimidazole (0.075 g, 0.46 mmol) was reacted according to GP7.Purified by flash CC (SiO₂; DCM/MeOH 20:1) to give the title compound(97KK09b) (0.055 g, 61%). ¹H-NMR (MeOD) δ 6.90-6.85 (m, 1H), 7.10-7.03(m, 1H).

3.49 5,7-Dichloro-6-methyl-3H-benzooxazol-2-one (97KK09c)

3,5-Dichloro-2-hydroxy-4-methylbenzoic acid (0.331 g, 1.72 mmol) andcarbonyldiimidazole (0.285 g, 1.76 mmol) were reacted according to GP7.Purified by flash CC (SiO₂; DCM/MeOH 20:1) to give the title compound(97KK09c) (0.240 g, 64%). ¹H-NMR (MeOD) δ 2.43 (s, CH₃), 7.05 (s, 1H).

3.50 6,7-Difluoro-3H-benzooxazol-2-one (97KK11)

3,4-Difluoro-2-hydroxybenzoic acid (0.329 g, 2.27 mmol) andcarbonyldiimidazole (0.390 g, 2.41 mmol) were reacted according to GP7.Purified by flash CC (SiO₂; DCM/MeOH 40:1) to give the title compound(97KK11) (0.139 g, 36%). ¹H-NMR (MeOD) δ 6.83-6.80 (m, 1H), 7.08-7.01(m, 1H); ¹³C-NMR (MeOD) δ 105.6 (J=4.5 Hz, J=7.8 Hz), 112.6 (J=20.3 Hz),129.6, 133.1 (J=4.5 Hz, J=10.3 Hz), 136.7 (J=17.8 Hz, J=250.3 Hz), 148.1(J=10.0 Hz, J=240.0 Hz), 156.3.

3.51 General Procedure 8 (GP8)

A 4 ml vial was charged with carboxylic acid (1 equiv),diphenylphosphoryl azide (1 equiv), triethylamine (1 equiv), and toluene(4 ml). The mixture was shaken at 110° under an Argon atmosphere for 20h. The reaction mixture was cooled to r.t., water added (1 ml), and theproduct was extracted into ethyl acetate (2×1 ml). The combined org.layer was concentrated in vacuo before being purified by using an IscoCombiFlasch Sq 16× to give the product.

3.52 7-Methyl-3H-benzooxazol-2-one (86KK37a)

2-Hydroxy-3-methylbenzoic acid (0.303 g, 1.99 mmol), diphenylphosphorylazide (0.548 g, 1.99 mmol), and Et₃N (0.201 g, 1.99 mmol) were reactedaccording to GP8. Purified by using an Isco CombiFlash Sq 16× [10 gsilica column, eluting 0-50% EtOAc in n-heptane (31 min) then 50% EtOAcin n-heptane (20 min)] to give the title compound (86KK37a) (0.204 g,69%). ¹H-NMR (CDCl₃) δ 2.39 (s, CH₃), 7.08-7.04 (m, 1H), 6.94-6.92 (m,2H), 9.29 (br. s, 1H); ¹³C-NMR (CDCl₃) δ 14.7, 107.7, 121.0, 124.1,124.5, 129.1, 142.9, 156.2.

3.53 7-Isopropyl-3H-benzooxazol-2-one (86KK37b)

2-Hydroxy-3-isopropylbenzoic acid (0.342 g, 1.90 mmol),diphenylphosphoryl azide (0.523 g, 1.90 mmol), and Et₃N (0.192 g, 1.90mmol) were reacted according to GP8. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-50% EtOAc in n-heptane(31 min) then 50% EtOAc in n-heptane (20 min)] to give the titlecompound (97KK37b) (0.263 g, 78%). ¹H-NMR (CDCl₃) δ 1.33 (d, J=7.0, 2CH₃), 3.24 (p, J=7.0, CH), 7.00-6.94 (m, 2H), 7.12-7.10 (m, 1H), 9.58(br. S, 1H); ¹³C-NMR (CDCl₃) δ 22.5, 28.9, 107.8, 120.6, 124.4, 129.3,131.9, 141.8, 156.5.

3.54 5,7-Diisopropyl-3H-benzooxazol-2-one (86KK39a)

2-Hydroxy-3,5-diisopropylbenzoic acid (0.378 g, 1.70 mmol),diphenylphosphoryl azide (0.468 g, 1.70 mmol), and Et₃N (0.172 g, 1.70mmol) were reacted according to GP8. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-50% EtOAc in n-heptane(41 min) then 50% EtOAc in n-heptane (10 min)] to give the titlecompound (86KK39a) (0.234 g, 63%). ¹H-NMR (CDCl₃) δ 1.25 (d, J=7.0,CH₃), 1.25, (d, J=6.8, CH₃), 1.34 (d, J=6.8, CH₃), 1.34 (d, J=7.0, CH₃),2.94-2.87 (m, CH), 3.24-3.17 (m, CH), 6.89-6.83 (m, 2H), 10.23 (br. S,1H); ¹³C-NMR (CDCl₃) δ 22.6, 24.5, 29.4, 34.6, 105.9, 118.9, 129.6,131.2, 140.1, 145.7, 157.3.

3.55 5-7-Dibromo-3H-benzooxazol-2-one (86KK39c)

3,5-Dibromo-2-hydroxybenzoic acid (0.477 g, 1.61 mmol),diphenylphosphoryl azide (0.443 g, 1.61 mmol), and Et₃N (0.163 g, 1.61mmol) were reacted according to GP8. Purified by using an IscoCombiFlash Sq 16× [(10 g silica column, eluting 0-50% EtOAc in n-heptane(31 min) then 50% EtOAc in n-heptane (20 min)] to give the titlecompound (86KK39d) (0.345 g, 73%). ¹H-NMR (MeOD+CDCl₃) δ 7.17 (s, 1H),7.38 (s, 1H); ¹³C-NMR (MeOD+CDCl₃) δ 103.2, 113.0, 117.4, 128.3, 133.3,142.4, 155.2.

3.56 6-Methoxy-3H-benzooxazol-2-one (86KK39d)

2-Hydroxy-4-methoxybenzoic acid (0.433 g, 2.58 mmol), diphenylphosphorylazide (0.548 g, 2.58 mmol), and Et₃N (0.261 g, 2.58 mmol) were reactedaccording to GP8. Purified by using an Isco CombiFlash Sq 16× [(10 gsilica column, eluting 0-50% EtOAc in n-heptane (31 min) then 50% EtOAcin n-heptane (20 min)] to give the title compound (86KK39d) (0.216 g,50%). ¹H-NMR (DMSO) δ 3.70 (s, OCH₃), 6.70-6.68 (m, 1H), 6.97-6.94 (m,2H), 11.36 (br. s, 1H); ¹³C-NMR (DMSO) δ 56.5, 97.7, 109.9, 110.6,124.3, 144.7, 155.5, 155.9.

3.57 4,6-Dimethoxy-3H-benzooxazol-2-one (86KK39e)

2-Hydroxy-4,6-dimethoxybenzoic acid (0.456 g, 2.30 mmol),diphenylphosphoryl azide (0.633 g, 2.30 mmol), and Et₃N (0.233 g, 2.30mmol) were reacted according to GP8. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-50% EtOAc in n-heptane(31 min) then 50% EtOAc in n-heptane (20 min)] to give the titlecompound (86KK39e) (0.050 g, 11%). ¹H-NMR (DMSO) δ 3.71 (s, OCH₃), 3.81(s, OCH₃), 6.41 (d, J=2.2, 1H), 6.56 (d, J=2.2 Hz, 1H), 11.50 (br. s,1H); ¹³C-NMR (DMSO) δ 56.5, 56.6, 89.8, 95.6, 113.0, 144.9, 145.0,155.4, 156.7.

3.58 4,5,7-Trichloro-3H-benxooxazol-2-one (97KK26)

3,5,6-Trichloro-2-hydroxybenzoic acid (0.498 g, 2.06 mmol),diphenylphosphoryl azide (0.567 g, 2.06 mmol), and Et₃N (0.208 g, 2.06mmol) were reacted according GP8. Purified by using an Isco CombiFlashSq 16× [10 g silica column, eluting 0-30% EtOAc in n-heptane (43 min)then 30% EtOAc in n-heptane (10 min)] to give the title compound(97KK26) (0.344 g, 70%). ¹H-NMR (MeOD) δ 7.24 (s, 1H); ¹³C-NMR (MeOD) δ113.3, 114.8, 123.8, 128.8, 132.3, 140.4, 155.0.

3.59 5,7-Diiodo-3H-benzooxazol-2one (92LH49)

A 4 ml vial was charged with 2-hydroxy-3,5-diiodobenzoic acid (0.780 g,2.00 mmol), diphenylphosphoryl azide (0.202 g, 1.99 mmol), triethylamine(0.550 g, 2.00 mmol), and toluene (4 ml). The mixture was shaken at 110°under an Argon atmosphere for 20 h. The reaction mixture was cooled tor.t., water added (1 ml), and the product was extracted into ethylacetate (2×1 ml). The combined org. layer was concentrated in vacuobefore being purified twice by flash CC (SiO₂; DCM/MeOH 9:1 and thenn-heptan/EtOAc 1:1) to give the title compound (92LH49) (0.205 g, 26%).¹-NMR (DMSO) δ 7.34-7.32 (m, 1H), 7.71-7.70 (m, 1H), 11.96 (br. s, 1H);¹³C-NMR (DMSO) δ 75.3, 88.0, 117.7, 131.6, 136.8, 144.9, 152.6.

3.60 4-methoxy-3H-benzooxazol-2-one (92LH58)

A 4 ml vial was charged with 2-hydroxy-6-methoxybenzoic acid (0.336 g,2.00 mmol), diphenylphosphoryl azide (0.202 g, 1.99 mmol), triethylamine(0.550 g, 2.00 mmol), and toluene (4 ml). The mixture was shaken at 110°under an Argon atmosphere for 20 h. The reaction mixture was cooled tor.t., water added (1 ml), and the product was extracted into ethylacetate (2×1 ml). The combined org. layer was concentrated in vacuo givethe crude title compound (92LH58) (0.345 g)

3.61 7-Nitro-3H-benzooxazol-2-one (92LH59)

A 4 ml vial was charged with 2-hydroxy-3-nitrobenzoic acid (0.66 g, 2.00mmol), diphenylphosphoryl azide (0.202 g, 1.99 mmol), triethylamine(0.550 g, 2.00 mmol), and toluene (4 ml). The mixture was shaken at 110°under an Argon atmosphere for 20 h. The reaction mixture was cooled tor.t., water added (1 ml), and was extracted with ethyl acetate (2×1 ml).The water phase was added SiO₂ and concentrated in vacuo. The productwas purified by flash CC (SiO₂; EtOAc) to give the title compound(92LH59) (0.230 g, 64%). ¹H-NMR (DMSO) δ 7.42 7.30 (m, 2H), 7.86-7.84(m, 1H).

3.62 4-Methyl-7-isopropyl-3H-benzooxazol-2-one (92LH71)

A 4 ml vial was charged with 2-hydroxy-3-isopropyl-6-methylbenzoic acid(0.389 g, 2.00 mmol), diphenylphosphoryl azide (0.202 g, 1.99 mmol),triethylamine (0.550 g, 2.00 mmol), and toluene (4 ml). The mixture wasshaken at 110° under an Argon atmosphere for 20 h. The reaction mixturewas cooled to r.t., water added (1 ml), and the product was extractedinto ethyl acetate (2×1 ml). The combined org. layer was concentrated invacuo before being purified by prep. RP-HPLC [conditions: stationaryphase, Luna 15 um C18; column, 250×21.2 mm; mobile phase, 20 ml/min,H₂O/CH₃CN, ammoniumacetate buffer (25 nM)] to give the title compound(92LH71) (0.100 g, 26%). ¹H-NMR (CDCl₃) δ 1.34-1.29 (m, 6H), 2.37-2.35(m, 3H), 3.22-3.17 (m, 1H), 6.94-6.87 (m, 2H9, 10.70 (br. s, 1H);¹³C-NMR (CDCl₃) δ 15.8, 22.5, 28.8, 118.0, 120.2, 125.4, 128.6, 129.0,141.4, 157.4.

3.63 7-Methyl-4-isopropyl-3H-benzooxazol-2-one (92LH76)

A 4 ml vial was charged with 2-hydroxy-3-methyl-6-isopropylbenzoic acid(0.389 g, 2.00 mmol), diphenylphosphoryl azide (0.202 g, 1.99 mmol),triethylamine (0.550 g, 2.00 mmol), and toluene (4 ml). The mixture wasshaken at 110° under an Argon atmosphere for 20 h. The reaction mixturewas cooled to r.t., water added (1 ml), and the product was extractedinto ethyl acetate (2×1 ml). The combined org. layer was concentrated invacuo before being purified by prep. RP-HPLC [conditions: stationaryphase, Luna 15 um C18; column, 250×21.2 mm; mobile phase, 20 ml/min,H₂O/CH₃CN, ammoniumacetate buffer (25 nM)] to give the title compound(92LH76) (0.066 g, 17%). ¹H-NMR (MeOD) δ 1.25 (d, J=6.9 Hz, CH₃), 1.26(d, J=7.0 Hz, CH₃), 2.30 (s, CH₃), 3.01 (quint, J=6.9 Hz, CH), 6.95-6.86(m, 2H); ¹³C-NMR (CDCl₃) δ 14.2, 22.9, 30.1, 118.5, 121.4, 124.8, 128.6,129.9, 143.6, 157.6.

3.64 General Procedure 9 (GP9)

A reaction flask was charged with benzothiazol-2-one (1 equiv),chloroiodoalkane (1 equiv), and base (1.5 equiv) in MeCH (3 ml) andstirred at r.t. for 24 h. The reaction mixture was added water and theproduct extracted into CH₂Cl₂. The combined org. layer was dried overNa₂SO₄ and concentrated in vacuo before being purified by flash columnchromatography (CC).

3.65 3-(2-Chloroethyl)-3H-benzothiazol-2-one (62KK38)

2-Hydroxybenzothiazol (0.508 g, 3.29 mmol), 2-chloro-1-iodoethane (0.499g, 2.52 mmol), and K₂CO₃ (0.547 g, 3.96 mmol) in MeCN (10 ml) werereacted according to GP9. Purified by CC (Al₂O₃; DCM/n.heptane 1:2) togive the title compound (62KK38) (0.292 g, 54%).

3.66 3-(3-Chloropropyl)-3H-benzothiazol-2-one (62KK21)

2-Hydroxybenzothiazol (1.003 g, 6.50 mmol), 3-chloro-1-iodopropane(1.361 g, 6.66 mmol), and K₂CO₃ (1.021 g, 7.39 mmol) in MeCN (20 ml)were reacted according to GP9. Purified by CC (SiO₂; DCM/n.heptane 1:1)to give the title compound (62KK21) (0.847 g, 57%).

3.67 3-(4-Chlorobutyl)-3H-benzothiazol-2-one (62KK29)

2-Hydroxybenzothiazol (0.496 g, 3.22 mmol), 4-chloro-1-iodobutane (0.722g, 3.24 mmol), and K₂CO₃ (0.576 g, 4.17 mmol) in MeCN (13 ml) werereacted according to GP9. Purified by CC (SiO₂; DCM/n.heptane 1:1) togive the title compound (62KK30) (0.487 g, 63%).

3.68 3-(2-Chloroethyl)-3H-benzooxazol-2-one (62KK39)

3H-benzooxazol-2-one (0.425 g, 3.05 mmol), 2-chloro-1-iodoethane (0.563g, 2.84 mmol), and K₂CO₃ (0.647 g, 4.68 mmol) in MeCN (10 ml) werereacted according to GP9. Purified by CC (Al₂O₃; DCM/n-heptane 1:2) togive the title compound (62KK39) (0.158 g, 28%).

3.69 3-(3-Chloropropyl)-3H-benzooxazol-2-one (62KK30)

3H-benzooxazol-2-one (0.580 g, 4.16 mmol), 3-chloro-1-iodopropane (0.854g, 4.18 mmol), and K₂CO₃ (0.691 g, 5.00 mmol) in MeCN (10 ml) werereacted according to GP9. Purified by CC (SiO₂; DCM/n-heptane 1:1, DCM)to give the title compound (62KK30) (0.133 g, 14%).

3.70 3-(4-Chlorobutyl)-3H-benzooxazol-2-one (62KK28)

3H-benzooxazol-2-one (0.419 g, 3.01 mmol), 4-chloro-1-iodobutane (0.677g, 3.04 mmol), and K₂CO₃ (0.500 g, 3.62 mmol) in MeCN (12 ml) werereacted according to GP9. Purified by CC (SiO₂; DCM/n-heptane 1:1, DCM)to give the title compound (62KK28) (0.309 g, 45%).

3.71 3-(5-Chloropentyl)-3H-benzothiazol-2-one (107LH01)

2-Hydroxybenzothiazol (0.302 g, 2.0 mmol), 5-chloro-1-iodopentane (0.370g, 2.0 mmol), and Cs₂CO₃ (0.977 g, 3.0 mmol) were reacted according toGP9. Purified by flash CC (SiO₂; DCM) to give the title compound(107LH01) (0.461 g, 90%). ¹H NMR (CDCl₃) δ 1.59-1.53 (m, 2H), 1.87-1.75(m, 4H), 3.53 (t, J=6.6 Hz, CH₂), 3.96 (t, J=7.2 Hz, CH₂), 7.44-7.03 (m,4H); ¹³C NMR (CDCl₃) δ 24.2, 27.0, 32.2, 42.6, 44.7, 110.6, 122.8,123.0, 123.2, 126.4, 137.2, 170.0.

3.72 3-(6-Chlorohexyl)-3H-benzothiazol-2-one (107LH02)

2-Hydroxybenzothiazol (0.302 g, 2.0 mmol), 6-chloro-1-iodohexane (0.398g, 2.0 mmol), and Cs₂CO₃ (0.977 g, 3.0 mmol) were reacted according toGP9. Purified by flash CC (SiO₂; DCM) to give the title compound(107LH02) (0.491 g, 91%). ¹H NMR (CDCl₃) δ 1.53-1.40 (m, 4H), 1.80-1.73(m, 4H), 3.52 (t, J=6.6 Hz, CH₂), 3.95 (t, J=7.2 Hz, CH₂), 7.44-7.03 (m,4H); ¹³C NMR (CDCl₃) δ 26.2, 26.6, 27.6, 32.5, 42.7, 45.0, 110.6, 122.8,123.0, 123.1, 126.4, 137.2, 170.0.

3.73 General Procedure 10 (GP10)

A 4 ml vial was charged with benzooxazol-2-one (1 equiv),3-chloro-1-iodopropane (1.2 equiv), and Cs₂CO₃ (1.2 equiv) in CH₃CN (1ml) and shaken at r.t. for 20 h. The reaction mixture was added water (1ml) and the product extracted into EtOAc (2×1 ml). The combined organiclayer filtered through a WHATMAM FT 5.0 μm PTFE column and concentratedin vacuo before being purified by using an Isco CombiFlasch Sq 16× togive the product.

3.74 3-(3-Chloropropyl)-4-methyl-3H-benzooxazol-2-one (86KK21a)

Crude 4-methyl-3H-benzooxazol-2-one (86KK20a) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-25% EtOAc in n-heptane(33 min) then 25% EtOAc in n-heptane (10 min)] to give the titlecompound (86KK21a) (0.111 g). ¹H-NMR (CDCl₃) δ 2.37-2.21 (m, CH₂), 2.55(s, CH₃), 3.65 (t, J=6.1 Hz, CH₂), 4.14 (t, J=6.8 Hz, CH₂), 7.03-6.90(m, 3H); ¹³C-NMR (CDCl₃) δ 17.7, 32.6, 41.6, 41.9, 108.3, 120.0, 122.6,127.2, 128.9, 143.1, 155.2.

3.75 3-(3-Chloropropyl)-5,7-dimethyl-3H-benzooxazol-2-one (86KK21b)

Crude 5,7-dimethyl-3H-benzooxazol-2-one (86KK20b) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-25% EtOAc in n-heptane(33 min) then 25% EtOAc in n-heptane (10 min)] to give the titlecompound (86KK21b) (0.094 g). ¹H-NMR (CDCl₃) δ 2.28-2.21 (m, CH₂), 2.32(s, CH₃), 2.35 (s, CH₃), 3.59 (t, J=5.9 Hz, CH₂), 3.94 (t, J=6.7 Hz,CH₂), 6.68 (s, 1H), 6.73 (s, 1H); ¹³C-NMR (CDCl₃) δ 14.6, 21.7, 30.9,39.7, 42.0, 106.4, 120.4, 124.9, 130.9, 133.9, 139.5, 155.1.

3.76 3-(3-Chloropropyl)-6-methyl-3H-benzooxazol-2-one (86KK21c)

Crude 6-methyl-3H-benzooxazol-2-one (86KK20c) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-25% EtOAc in n-heptane(33 min) then 25% EtOAc in n-heptane (3 min)] to give the title compound(86KK21c) (0.092 g). ¹H-NMR (CDCl₃) δ 2.28-2.21 (m, CH₂), 2.38 (s, CH₃),3.58 (t, J=6.5 Hz, CH₂), 3.97 (t, J=6.7 Hz, CH₂), 7.01-6.92 (m, 3H);¹³C-NMR (CDCl₃) δ 21.6, 30.9, 39.7, 41.9, 108.0, 111.0, 124.5, 129.0,133.0, 143.0, 154.8.

3.77 3-(3-Chloropropyl)-5-methyl-3H-benzooxazol-2-one (86KK21d)

Crude 5-methyl-3H-benzooxazol-2-one (86KK20d) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-25% EtOAc in n-heptane(33 min) then 25% EtOAc in n-heptane (3 min)] to give the title compound(86KK21d) (0.062 g). ¹H-NMR (CDCl₃) δ 2.29-2.22 (m, CH₂), 2.40 (s, CH₃),3.60 (t, J=5.9 Hz, CH₂), 3.97 (t, J=6.7 Hz, CH₂), 6.91-6.87 (m, 2H),7.07-7.05 (m, 1H); ¹³C-NMR (CDCl₃) δ 21.7, 30.9, 39.7, 41.9, 109.0,109.9, 123.1, 131.3, 134.2, 140.9, 155.0.

3.78 5-t-Butyl-3-(3-Chloropropyl)-3H-benzooxazol-2-one (86KK21e)

Crude 5-t-butyl-3H-benzooxazol-2-one (86KK20e) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-25% EtOAc in n-heptane(33 min) then 25% EtOAc in n-heptane (3 min)] to give the title compound(86KK21e) (0.102 g). ¹H-NMR (CDCl₃) δ 1.35 (br. s, C(CH₃)₃), 2.31-2.25(m, CH₂), 3.61 (t, J=5.9 Hz, CH₂), 4.02 (t, J=6.7, CH₂), 7.14-7.10 (m,3H). ¹³C-NMR (CDCl₃) δ 31.1, 31.9, 35.2, 39.4, 42.0, 105.7, 109.6,119.6, 131.2, 140.8, 148.0, 155.1.

3.79 3-(3-Chloropropyl)-6-chloro-3H-benzooxazol-2-one (86KK21f)

Crude 6-Chloro-3H-benzooxazol-2-one (86KK20f) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-20% EtOAc in n-heptane(33 min) then 20% EtOAc in n-heptane (3 min)] to give the title compound(86KK21f) (0.200 g). ¹H-NMR (CDCl₃) δ 2.22-2.16 (m, CH₂), 3.52 (t, J=5.9Hz, CH₂), 3.93 (t, J=6.6 HZ, CH₂), 6.94-6.92 (m, 1H), 7.19-7.11 (m, 2H);¹³C-NMR (CDCl₃) δ 30.2, 39.3, 41.2, 108.4, 110.8, 123.8, 127.8, 129.6,142.6, 153.8.

3.80 3-(3-Chloropropyl)-5-methoxy-3H-benzooxazol-2-one (86KK21i)

Crude 5-methoxy-3H-benzooxazol-2-one (86KK20i) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-20% EtOAc in n-heptane(33 min) then 20% EtOAc in n-heptane (3 min)] to give the title compound(86KK21i) (0.079 g). ¹H-NMR (CDCl₃) δ 2.25-2.22 (m, CH₂), 3.60-3.57 (m,CH₂), 3.97-3.93 (m, CH₂), 3.80 (s, OCH₃), 6.65-6.58 (m, 2H), 7.07-7.04(m, 1H); ¹³C-NMR (CDCl₃) δ 30.7, 39.5, 41.8, 56.1, 95.6, 107.1, 110.4,132.0, 136.7, 155.1, 156.9.

3.81 3-(3-Chloropropyl)-6-fluoro-3H-benzooxazol-2-one (86KK21i)

Crude 6-fluoro-3H-benzooxazol-2-one (86KK20j) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-20% EtOAc in n-heptane(33 min) then 20% EtOAc in n-heptane (3 min)] to give the title compound(86KK21j) (0.157 g). ¹H-NMR (CDCl₃) δ 2.22-2.15 (m, CH₂), 3.53 (t, J=6.1Hz, CH₂), 3.92 (t, J=6.6 Hz, CH₂), 6.95-6.82 (m, 3H); ¹³C (CDCl₃) δ30.6, 39.7, 41.7, 99.5 (J=28.7 Hz), 108.3 (J=9.4 Hz), 110.5 (J=24.2 Hz),127.5 (J=1.9 Hz), 142.7 (J=13.6 Hz), 154.5, 158.8 (J=241.6).

3.82 3-(3-Chloropropyl)-5-fluoro-3H-benzooxazol-2-one (86KK21k)

Crude 5-fluoro-3H-benzooxazol-2-one (86KK20k) DMF solution,3-chloro-1-iodopropane (0.480 g, 1.47 mmol), and Cs₂CO₃ (0.299 g, 1.46mmol) were reacted according to GP10. Purified by using an IscoCombiFlash Sq 16× [10 g silica column, eluting 0-20% EtOAc in n-heptane(35 min) then 20% EtOAc in n-heptane (3 min)] to give the title compound(86KK21k) (0.078 g). ¹H-NMR (CDCl₃) δ 2.28 (quint, J=6.3 Hz, CH₂), 3.62(t, J=6.1 Hz, CH₂), 4.00 (t, J=6.7 Hz, CH₂), 6.87-6.80 (m, 2H),7.16-7.13 (m, 1H); ¹³C-NMR (CDCl₃) δ 30.6, 39.9, 41.7, 97.0 (J=29.7),108.8 (J=24.8), 110.8 (J=9.7), 132.1 (J=12.6), 138.6, 154.8, 159.7(J=242.0 Hz).

3.83 General Procedure 11 (GP11)

A 4 ml vial was charged with 3-H-benzooxazol-2-one (1 equiv),3-bromopropanol (1.2 equiv), diethyl azodicarboxylate (1.2 equiv), andtriphenylphosphine (1.2 equiv) in THF (2 ml). The mixture was stirred atr.t under an Argon atmosphere for 20 h. The reaction mixture wasconcentrated in vacuo before being purified by using an Isco CombiFlaschSq 16× to give the product.

3.84 3-(3-Bromopropyl)-6-methoxy-3H-benzooxazol-2-one (97KK01a)

6-Methoxy-3H-benzooxazol-2-one (86KK39d) (0.093 g, 0.56 mmol),3-bromopropan-1-ol (0.093 g, 0.67 mmol), diethyl azodicarboxylate (0.117g, 0.67 mmol), and PPh₃ (0.176 g, 0.67 mmol) in THF (4 ml) were reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-80% DCM in n-heptane (37 min) then 80% DCM inn-heptane (10 min)] to give the title compound (97KK01a) (0.114 g, 71%).¹H-NMR (MeOD+CDCl₃) δ 2.30 (m, CH₂), 3.44 (t, J=6.5, CH₂), 3.95 (t,J=6.9, CH₂), 6.78-6.75 (m, 1H), 6.85-6.84 (m, 1H), 7.05-7.03 (m, 1H);¹³C-NMR (MeOD+CDCl₃) δ 30.2, 31.5, 41.4, 56.4, 98.3, 109.5, 110.3,125.3, 144.1, 156.1, 157.3.

3.85 3-(3-Bromopropyl)-5,7-dibromo-3H-benzooxazol-2-one (97KK01b)

5,7-Dibromo-3H-benzooxazol-2-one (86KK39c) (0.138 g, 0.47 mmol),3-bromopropan-1-ol (0.078 g, 0.56 mmol), diethyl azodicarboxylate (0.098g, 0.56 mmol), and PPh₃ (0.148 g, 0.56 mmol) in THF (4 ml) was reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-60% DCM in n-heptane (36 min) then 60% DCM inn-heptane (15 min)] to give the title compound (97KK09b) (0.152 g, 87%).¹H-NMR (MeOD+CDCl₃) δ 2.35-2.30 (m, CH₂), 3.44 (t, J=6.3, CH₂), 3.96 (t,J=6.8 Hz, CH₂), 7.25 (s, 1H), 7.41 (s, 1H); ¹³C-NMR (MeOD+CDCl₃) δ 29.7,30.8, 41.8, 103.6, 111.4, 117.4, 128.5, 133.3, 140.4, 153.9.

3.86 3-(3-Bromopropyl)-7-methyl-3H-benzooxazol-2-one (97KK03a)

7-Methyl-3H-benzooxazol-2-one (86KK37a) (0.100 g, 0.67 mmol),3-bromopropan-1-ol (0.112 g, 0.80 mmol), diethyl azodicarboxylate (0.140g, 0.80 mmol), and PPh₃ (0.211 g, 0.80 mmol) in THF (4 ml) was reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-60% DCM in n-heptane (36 min) then 60% DCM inn-heptane (15 min)] to give the crude title compound (97KK03a) (0.072g). ¹H-NMR (MeOD) δ 2.31-2.26 (m, CH₂), 3.46 (t, J=6.5 Hz, CH₂), 3.94(t, J=6.6, CH₂), 7.10-6.91 (m, 3H).

3.87 3-(3-Bromopropyl)-7-isopropyl-3H-benzooxazol-2-one (97KK03b)

7-Isopropyl-3H-benzooxazol-2-one (86KK37b) (0.131 g, 0.74 mmol),3-bromopropan-1-ol (0.123 g, 0.89 mmol), diethyl azodicarboxylate (0.155g, 0.89 mmol), and PPh₃ (0.233 g, 0.89 mmol) in THF (4 ml) was reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-60% DCM in n-heptane (35 min) then 60% DCM inn-heptane (15 min)] to give the crude title compound (97KK03b) (0.089g). ¹H-NMR (MeOD) δ 1.29 (d, J=7.0, 2 CH₃), 2.29 (quint, J=6.7 Hz, CH₂),3.18 (sept, J=6.9 Hz, CH), 3.47 (t, J=6.5 Hz, CH₂), 3.97 (t, J=6.9,CH₂), 7.04-7.00 (m, 2H), 7.17-7.13 (m, 1H).

3.88 3-(3-Bromopropyl)-5,7-diisopropyl-3H-benzooxazol-2-one (97KK03c)

5,7-Diisopropyl-3H-benzooxazol-2-one (86KK39a) (0.110 g, 0.50 mmol),3-bromopropan-1-ol (0.083 g, 0.60 mmol), diethyl azodicarboxylate (0.104g, 0.60 mmol), and PPh₃ (0.157 g, 0.60 mmol) in THF (4 ml) was reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-60% DCM in n-heptane (35 min) then 60% DCM inn-heptane (15 min)] to give the crude title compound (97KK03c) (0.078g). ¹H-NMR (MeOD) δ 1.25 (d, J=6.8 Hz, 2 CH₃), 1.30 (d, J=7.0 Hz, 2CH₃), 2.30 (quint, 6.7 Hz, CH₂), 2.93 (sept, J=6.8 Hz, CH), 3.15 (sept,J=6.9 Hz, CH), 3.49 (t, J=6.5 Hz, CH₂), 3.98 (t, J=6.7 Hz, CH₂), 6.88(s, 1H), 6.96 (s, 1H).

3.89 3-(3-Bromopropyl)-4,6-dimethoxy-3H-benzooxazol-2-one (97KK05b)

4,6-Dimethoxy-3H-benzooxazol-2-one (86KK39e) (0.050 g, 0.26 mmol),3-bromopropan-1-ol (0.043 g, 0.31 mmol), diethyl azodicarboxylate (0.54g, 0.31 mmol), and PPh₃ (0.82 g, 0.31 mmol) in THF (4 ml) was reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-60% DCM in n-heptane (35 min) then 60% DCM inn-heptane (15 min)] to give the title compound (97KK05b) (0.035 g, 43%).¹H-NMR (MeOD) δ 2.30 (quint, J=6.7 Hz, CH₂), 3.43 (t, J=6.6 Hz, CH₂),3.77 (s, OCH₃), 3.88 (s, OCH₃), 4.07 (t, J=6.8 Hz, CH₂), 6.47-6.37 (m,2H).

3.90 3-(3-Bromopropyl)-7-fluoro-3H-benzooxazol-2-one (97KK12a)

7-Fluoro-3H-benzooxazol-2-one (97KK09a) (0.186 g g, 1.21 mmol),3-bromopropan-1-ol (0.202 g, 1.45 mmol), diethyl azodicarboxylate (0.253g, 1.45 mmol), and PPh₃ (0.381 g, 1.45 mmol) in THF (4 ml) was reactedaccording to GP11. Purified by using an Isco CombiFlash Sq 16× [4 gsilica column, eluting 0-50% DCM in n-heptane (46 min) then 50% DCM inn-heptane (10 min)] to give the title compound (97KK12a) (0.100 g, 30%).¹H-NMR (CDCl₃) δ 2.32-2.26 (m, CH₂), 3.38 (t, J=6.1 Hz, CH₂), 3.94 (t,J=6.9 Hz, CH₂), 6.87-6.82 (m, 1H), 7.10-7.05 (m, 2H); ¹³C-NMR (CDCl₃′) δ29.8, 30.8, 41.4, 104.4 (J=3.9 Hz), 110.8 (J=16.8 Hz), 124.8 (J=7.1 Hz),139.8 (J=14.5 Hz), 133.8 (J=4.8 Hz), 146.2 (J=250.3 Hz), 154.0

3.91 3-(3-Bromopropyl)-5,7-dichloro-6-methyl-3H-benzooxazol-2-one(97KK12b)

5,7-Dichloro-6-methyl-3H-benzooxazol-2-one (97KK09c) (0.239 g g, 1.10mmol), 3-bromopropan-1-ol (0.183 g, 1.32 mmol), diethyl azodicarboxylate(0.230 g, 1.32 mmol), and PPh₃ (0.346 g, 1.32 mmol) in THF (4 ml) wasreacted according to GP11. Purified by using an Isco CombiFlash Sq 16×[4 g silica column, eluting 0-50% DCM in n-heptane (46 min) then 50% DCMin n-heptane (10 min)] to give the crude title compound (97KK12b) (0.051g).

3.92 General Procedure 12 (GP12)

The heterocycle (1 equiv) and NaI (2 equiv) in acetone (1 ml per mmol)were heated to 50° C. for 72 h then cooled to r.t. Aqueous sodiumthiosulphate solution (10-20 ml) was added and the product was extractedinto EtOAc (2×20-100 ml). The organic layer was dried (K₂CO₃), filteredand concentrated in vacuo before being purified.

3.93 1-(2-Iodoethyl)-1,3-dihydrobenzoimidazol-2-one (56NK93)

1-(2-Chloroethyl)-1,3-dihydrobenzoimidazol-2-one (178 mg, 0.905 mmol)was used according to GP12. The crude product was purified using an IscoCombiFlash Sq 16× [4.1 g silica column, eluting heptane (5 min), 0-40%EtOAc in heptane (20 min), 40% EtOAc in heptane (10 min)] to give thetitle compound (56NK93) as a pale yellow oil (204 mg, 78%). ¹H NMR(CDCl₃) δ 9.26 (br. s, 1H), 7.10 (m, 3H), 7.04 (m, 1H), 4.28 (t, J=7.6Hz, 2H), 3.44 (t, J=7.6 Hz, 2H); HPLC-MS (ammonium acetate)[M+H]⁺=289.0.

3.94 1-(4-Iodobutyl)-1,3-dihydrobenzoimidazol-2-one (56NK94)

1-(4-Chlorobutyl)-1,3-dihydrobenzoimidazol-2-one (456 mg, 2.03 mmol) wasused according to GP12. The crude product was purified using an IscoCombiFlash Sq 16× [10 g silica column, eluting heptane (2 min), 0-40%EtOAc in heptane (31 min), 40% EtOAc in heptane (15 min)] to give thetitle compound (56NK94) as a pale yellow oil (491 mg, 77%). ¹H NMR(CDCl₃) δ 9.28 (br. s, 1H), 7.10 (m, 3H), 7.02 (m, 1H), 3.92 (m, 2H),3.25 (m, 2H), 1.92 (m, 4H); HPLC-MS (ammonium acetate) [M+H]⁺=317.0.

3.95 1-(3-Iodopropyl)-1,3-dihydrobenzoimidazol-2-one (56NK36)

1-(3-Chloropropyl)-1,3-dihydrobenzoimidazol-2-one (10.5 g, 50 mmol) wasused according to GP12. The crude product was recrystallised from EtOActo give the title compound (56NK36) as a while powder (12.15 g, 80%). ¹HNMR (CDCl₃) δ 9.93 (br. s, 1H), 7.11 (m, 1H), 4.00 (t, J=6.2 Hz, 2H),3.22 (t, J=6.8 Hz, 2H), 2.34 (pent, J=6.8 Hz, 2H); HPLC-MS (ammoniumacetate) [M+H]⁺=302.1.

3.96 1-(3-Iodopropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (56NK85)

1-(3-Chloropropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (852 mg, 3.79mmol) was used according to GP12. The crude product was purified usingan Isco CombiFlash Sq 16× [10 g silica column, eluting heptane (1 min),0-40% EtOAc in heptane (25 min), 40% EtOAc in heptane (10 min)] to givethe title compound (56NK85) as a pale yellow oil (1.02 g, 86%). ¹H NMR(CDCl₃) δ 7.10 (m, 3H), 6.98 (m, 1H), 3.98 (t, J=6.8 Hz, 2H), 3.42 (s,3H), 3.20 (t, J=6.8 Hz, 2H), 2.31 (pent, J=6.8 Hz, 2H); ¹³C NMR (CDCl₃)6154.30, 130.01, 129.23, 121.28, 107.48, 107.47, 41.59, 32.40, 27.06,2.17; HPLC-MS (ammonium acetate) [M+H]⁺=317.0.

3.97 1-(2-Chloroethyl)-1,3-dihydrobenzoimidazol-2-one (56NK91)

Sodium hydride (400 mg, 10 mmol, 60% in oil) was washed with dry DMF (10ml) under an argon atmosphere then DMF (10 ml) was added. The slurry ofNaH in DMF was added slowly to 2-hydroxybenzimidazole (1.34 g, 10 mmol)in DMF (10 ml) at 0° C. under argon. The reaction was stirred at 0° C.for 20 min then 1-chloro-2-iodoethane (1.90 g, 10 mmol) in DMF (5 ml)was added slowly. The reaction was stirred at r.t. for 1.5 h then water(10 ml) was added and the reaction acidified with HCl (2M, few drops)then made basic with aqueous sodium hydrogen carbonate solution. Theproduct was extracted with EtOAc (3×30 ml) and the organic layer waswashed with aqueous sodium thiosulphate solution (10 ml), aqueousmagnesium sulphate solution (4%, 2×10 ml), brine (10 ml), dried (K₂CO₃),filtered and concentrated in vacuo before being purified by using anIsco CombiFlash Sq 16× [10 g silica column, eluting heptane (5 min),0-40% EtOAc in heptane (35 min), 40% EtOAc in heptane (20 min)] to givethe title compound (56NK91) as a pale yellow oil (162 mg, 8%). ¹H NMR(CDCl₃) δ 8.70 (br. s, 1H), 7.09 (m, 4H), 4.22 (t, J=6.5 Hz, 2H), 3.84(t, J=6.5 Hz, 2H); ¹³C NMR (CDCl₃) δ 155.11, 130.28, 127.74, 121.91,121.60, 109.63, 108.45, 42.75, 41.16.

3.98 1-(4-Chlorobutyl)-1,3-dihydrobenzoimidazol-2-one (56NK92)

Sodium hydride (400 mg, 10 mmol, 60% in oil) was washed with dry DMF (10ml) under an argon atmosphere then DMF (10 ml) was added. The slurry ofNaH in DMF was added slowly to 2-hydroxybenzimidazole (1.34 g, 10 mmol)in DMF (10 ml) at 0° C. under argon. The reaction was stirred at 0° C.for 20 min then 1-chloro-4-iodobutane (2.18 g, 10 mmol) in DMF (5 ml)was added slowly. The reaction was stirred at r.t. for 1.5 h then water(10 ml) was added and the reaction acidified with HCl (2M, few drops)then made basic with aqueous sodium hydrogen carbonate solution. Theproduct was extracted with EtOAc (3×30 ml) and the organic layer waswashed with aqueous sodium thiosulphate solution (10 ml), aqueousmagnesium sulphate solution (4%, 2×10 ml), brine (10 ml), dried (K₂CO₃),filtered and concentrated in vacuo before being purified by using anIsco CombiFlash Sq 16× [10 g silica column, eluting heptane (5 min),0-40% EtOAc in heptane (35 min), 40% EtOAc in heptane (20 min)] to givethe title compound (56NK92) as a pale yellow oil (416 mg, 19%). ¹H NMR(CDCl₃) δ 10.48 (br. s, 1H), 7.26-7.00 (m, 4H), 3.95 (t, J=6.8 Hz, 2H),3.59 (t, J=6.3 Hz, 2H), 1.97 (m, 2H), 1.87 (m, 2H); ¹³C NMR (CDCl₃) δ158.88, 130.08, 128.14, 121.56, 121.25, 109.82, 107.74, 44.32, 39.88,29.53, 25.66; HPLC-MS (ammonium acetate) [M+H]⁺=225.2.

3.99 1-(3-Chloropropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (56NK01)

1-(3-Chloropropyl)-1,3-dihydrobenzoimidazol-2-one (2.10 g, 10 mmol),methyl iodide (1.5 ml, 25 mmol), sodium hydroxide (2 M, 5 ml, 10 mmol)and MeCN (10 ml) were stirred at r.t. 18 h. Water (10 ml) was added andthe product was extracted into EtOAc (2×30 ml). The organic layer waswashed with aqueous sodium thiosulphate solution (5 ml), brine (10 ml),dried (K₂CO₃), filtered and concentrated in vacuo before being purifiedby using an Isco CombiFlash Sq 16× [35 g silica column, eluting heptane(1 min), 0-50% EtOAc in heptane (40 min), 50% EtOAc in heptane (40 min)]to give the title compound (56NK01) as a pale yellow oil (1.93 g, 86%).¹H NMR (CDCl₃) δ 7.10 (m, 3H), 6.98 (m, 1H), 4.06 (t, J=6.6 Hz, 2H),3.85 (t, J=6.6 Hz, 2H), 3.42 (s, 3H), 2.25 (pent, J=6.6 Hz, 2H); HPLC-MS(ammonium acetate) [M+H]⁺=225.1.

3.100 3-(4-Chlorobutyl)-3H-benzooxazole-2-thione (56NK132)

Iodine (127 mg, 0.5 mmol) in DMF (2 ml) was added to2-(4-chlorobutylsulfanyl)-benzooxazole (697 mg, 2.88 mmol) and thereaction was heated to 125° C. for 24 h then cooled to r.t. Aqueoussodium thiosulplate solution (5 ml) was added and the product wasextracted with ether (3×30 ml). The organic phase was washed withaqueous magnesium sulphate solution (4%, 2×10 ml), brine (10 ml), dried(K₂CO₃), filtered and concentrated in vacuo. The crude product waspurified using an Isco CombiFlash Sq 16× [4.1 g silica column, elutingheptane (3 min), 0-10% EtOAc in heptane (25 min), 10% EtOAc in heptane(2 min)] to give the title compound (56NK132) as a white powder (68 mg,10%). ¹H NMR (CDCl₃) δ 7.36 (m, 1H), 7.28 (m, 2H), 7.13 (m, 1H), 4.25(t, J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.06 (m, 2H), 1.92 (m, 2H).

3.101 1-(3-Chloropropyl)-1H-indol-2,3-dione (85LM02)

A 500 ml flask was charged with 1H-indol-2,3-dione (isatin) (3.62 g, 25mmol), 1-chloro-3-iodopropan (2.8 ml, 27 mmol) and Cs₂CO₃ (18 g, 55mmol) in MeCN (200 ml). The mixture was stirred 40° C. for 48 hours.Water (50 ml) and EtOAc (50 ml) were added and the phases wereseparated. The aqueous phase was re-extracted with EtOAc (50 ml). Thecombined org. layer were dried (Na₂SO₄) and evaporated to dryness. Thecrude product was purified by to column chromatography (SiO₂;EtOAc/n-heptane 1:4) to give the title compound (85LM02) (4.2 g, 80%).¹H NMR (CDCl₃) δ 2.20 (qv, 2H), 3.60 (t, 2H), 3.90 (t, 2H), 7.00 (d,1H), 7.15 (t, 1H), 7.55-7.65 (m, 2H); HPLC-MS (ammonium acetate)[M+H]⁺=224.2.

3.102 1-(3-Iodopropyl)-1H-indol-2,3-dione (85LM05)

A 50 ml flask, charged with compound1-(3-chloropropyl)-1H-indol-2,3-dione (85LM02) (0.232 g, 1 mmol) and NaI(0.327 g, 2.2 mmol) in acetone (10 ml), was stirred at 50° C. for 24hours. Water (10 ml) was added and the phases were separated. Theaqueous phase was re-extracted with acetone (10 ml). The combinedorganic phases were dried (Na₂SO₄) and evaporated to dryness to give thecrude title compound (85LM05) (0.294 g). ¹H NMR (CDCl₃) δ 2.20 (qv, 2H),3.20 (t, 2H), 3.80 (t, 2H), 7.0 (d, 1H), 7.15 (t, 1H), 7.55-7.65 (m,2H).

3.103 3-(1H-Indol-3-yl)propan-1-ol (85LM16B)

A suspension of LiAlH₄ (2.48 g, 65 mmol) in dry THF (140 ml) was stirredin a 500 ml flask. 3-(1H-indol-3-yl)propionic acid (5.38 g, 28 mmol) wasdissolved in dry THF (20 ml) and added slowly. The mixture was heated to35° C. Stirring was continued for 2 hours at 35° C. and overnight atroom temperature. Water (20 ml) was added drop wise and very slowly,followed by addition of H₂O/H₂SO₄ (1:1) (50 ml). To the resultingmixture NaOH was added (until pH 7) and the two phases were separated.The organic phase was dried (Na₂SO₄) and evaporated to dryness to givethe crude title compound (85LM16B) (5.0 g). The material was used forthe next reaction step without further purification. ¹H NMR (CD₃OD) δ1.92 (qv, 2H), 2.80 (t, 2H), 3.61 (t, 2H), 7.00 (t, 1H), 7.05 (t, 1H),7.33 (d, 1H), 7.55 (d, 1H).

3.104 Toluene-4-sulfonic acid 3-(1H-indol-3-yl)propyl ester (85LM17)

Crude 3-(1H-indol-3-yl)propan-1-ol (85LM16B) (5.0 g, 29 mmol) andpyridine (10 ml, 160 mmol) was dissolved in dry THF (140 ml) in a 100 mlflask. The mixture was cooled to −78° C. and p-toluenesulfonyl chloride(10.9 g, 57 mmol) dissolved in dry THF (10 ml) was slowly added followedby stirring at −78° C. for 1 hour and then heating to room temperatureover a period of 20 minutes. The solution was washed with H₂SO₄ (10 ml,1M) then saturated aqueous sodium bicarbonate (10 ml) and finally water(10 ml). The organic phase was dried (Na₂SO₄) and evaporated to drynessto give the crude title compound (85LM17) (4.0 g). The material was usedfor the next reaction step without further purification.

3.105 3-(3-Bromo-2-hydroxypropyl)-3H-benzothiazol-2-one (85LM04)

A 50 ml flask, charged with 2-hydroxybenzothiazol (0.650 g, 4.3 mmol),1,3-dibromo-2-propanol (0.22 ml, 2.2 mmol) and Cs₂CO₃ (3.0 g, 9.2 mmol)in MeCN (20 ml), was stirred at 40° C. for 24 hours. Water (10 ml) andEtOAc (10 ml) were added and the phases were separated. The aqueousphase was re-extracted with EtOAc (10 ml). The combined organic phaseswere dried (Na₂SO₄) and evaporated to dryness to give the crude titlecompound (85LM04) (0.308 g). The material was used for the next reactionstep without further purification.

3.106 3-(3-Chloro-2-methyl-propyl)-3H-benzothiazol-2-one (85LM13)

A 50 ml flask, charged with 2-hydroxybenzothiazol (0.603 g, 4.0 mmol),1-bromo-3-chloro-2-methylpropan (0.56 ml, 4.8 mmol) and Cs₂CO₃ (2.86 g,8.8 mmol) in CH₃CN (20 ml), was stirred at 40° C. for 24 hours. Water(10 ml) and EtOAc (10 ml) were added and the phases were separated. Theaqueous phase was re-extracted with EtOAc (10 ml). The combined organicphases were dried (Na₂SO₄) and evaporated to dryness. The crude productwas subjected to column chromatography (SiO₂; EtOAc/n-heptane 1:8) togive the title compound (85LM13) (0.769 g, 80%). ¹H NMR (CDCl₃) δ 1.10(d, 3H), 2.45 (octet, 1H), 3.55 (d, 2H), 3.90 (dd, 1H), 4.05 (dd, 1H),7.10-7.20 (m, 2H), 7.35 (t, 1H), 7.40 (d, 1H); HPLC-MS (ammoniumacetate) [M+H]⁺=242.1.

3.107 General Procedure 13 (GP13)

A 100 ml flask, charged with either (R)- or(S)-3-bromo-2-methyl-propanol (1 equiv), 2-hydroxybenzothiazol (1 equiv)mmol), and Cs₂CO₃ (1 equiv) in MeCN (30 ml), was stirred at 50° C. for48 hours. Water (20 ml) and EtOAc (20 ml) were added and the phases wereseparated. The aqueous phase was re-extracted with EtOAc (20 ml). Thecombined org. layer was dried (Na₂SO₄) and concentrated in vacuo to givethe crude product. The material was used for the next reaction stepwithout further purification.

3.108 3-((R)-3-Hydroxy-2-methylpropyl)-3H-benzothiazol-2-one (85LM72-60)

(S)-3-Bromo-2-methylpropanol (0.760 g, 5.0 mmol), 2-hydroxybenzothiazol(0.751 g, 5.0 mmol), and Cs₂CO₃ (1.6 g, 5.0 mmol) in MeCN (30 ml) werereacted according to GP13 to give the title crude compound (85LM72-60)(1.3 g).

3.109 3-((S)-3-Hydroxy-2-methylpropyl)-3H-benzothiazol-2-one (85LM89-76)

(R)-3-Bromo-2-methylpropanol (0.760 g, 5.0 mmol), 2-hydroxybenzothiazol(0.751 g, 5.0 mmol), and Cs₂CO₃ (1.6 g, 5.0 mmol) in MeCN (30 ml) werereacted according to GP13 to give the title crude compound (85LM89-76)(1.3 g).

3.110 General Procedure 14 (GP14)

3-Hydroxyalkyl-3H-benzothiazol-2-one (1 equiv) and pyridine (4 equiv)was dissolved in dry DCM (50 ml) in a 100 ml flask. The mixture wasstirred and cooled to −78° C. followed by slow addition ofp-toluenesulfonyl chloride (5 equiv) dissolved in dry DCM (10 ml).Stirring was continued at −78° C. for 1 hour and at room temperature for2 hours. The solution was washed with hydrochloric acid (10 ml, 1M) thensaturated aqueous sodium bicarbonate (10 ml) and finally water (10 ml).The organic phase was dried (Na₂SO₄) and evaporated to dryness. Thecrude product was purified by column chromatography (SiO₂; DCM).

3.111 Toluene-4-sulfonic acid(R)-2-methyl-3-(2-oxobenzothiazol-3-yl)-propyl ester (85LM73-61)

3-((R)-3-Hydroxy-2-methylpropyl)-3H-benzothiazol-2-one (85LM72-60) (1.3g, 2.8 mmol), pyridine (0.900 g, 11.4 mmol), and p-toluenesulfonylchloride (2.7 g, 14.2 mmol) were reacted according to GP14 to give thetitle compound (85LM73-61) (0.90 g, 48%-2 steps). ¹H NMR (CDCl₃) δ 1.0(d, 3H), 2.45 (m, 4H), 3.80-3.90 (m, 2H), 3.90-4.00 (m, 2H), 7.0 (d,1H), 7.15 (t, 1H), 7.25-7.35 (m, 3H), 7.40 (d, 1H), 7.75 (d, 2H).

3.112 Toluene-4-sulfonic acid(S)-2-methyl-3-(2-oxo-benzothiazol-3-yl)-propyl ester (85LM90-77)

3-((S)-3-Hydroxy-2-methylpropyl)-3H-benzothiazol-2-one (85LM89-76) (1.3g, 2.8 mmol), pyridine (0.900 g, 11.4 mmol), and p-toluenesulfonylchloride (2.7 g, 14.2 mmol) were reacted according to GP14 to give thetitle compound (85LM90-77) (0.90 g, 46%-2 steps). ¹H NMR (CDCl₃) δ 1.0(d, 3H), 2.45 (m, 4H), 3.80-3.90 (m, 2H), 3.90-4.00 (m, 2H), 7.0 (d,1H), 7.15 (t, 1H), 7.25-7.35 (m, 3H), 7.40 (d, 1H), 7.75 (d, 2H).

3.113 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80)

3-(3-Chloropropyl)-3H-benzothiazol-2-one (62KK21) (1.58 g, 6.94 mmol)was dissolved in acetone (10 mL) and NaI (2.08 g, 13.9 mmol) was added.The mixture was heated to 50° C. under stirring for 18 h. A saturatedaq. solution of Na₂S₂O₃ (5 mL) was added followed by extraction (EtOAc).The combined organic phase was dried (Na₂SO₄), filtered and concentratedin vacuo which gave the title compound (61KS80) (2.17 g, 98%) as acolourless oil which on prolonged standing crystallised to a whitepowder. This was sufficiently pure for further reaction. ¹H NMR (CDCl₃)□ 2.25 (q, 2H, J=7.0 Hz, —CH₂CH ₂CH₂I), 3.22 (t, 2H, J=7.0 Hz, —CH₂CH₂CH₂I), 4.04 (t, 2H, J=7.0 Hz, —CH ₂CH₂CH₂I), 7.13-7.46 (m, 4H, Ar); ¹³CNMR (CDCl₃) □ 0.0 (—CH₂CH₂ CH₂I), 29.8 (—CH₂ CH₂CH₂I), 41.7(—CH₂CH₂CH₂I), 108.8, 121.1, 121.1, 121.6, 124.8, 135.2 (Ar), 168.3(C═O).

3.114 General Procedure 15 (GP15)

A 4 ml vial was charged with 3-chloroalkyl-3H-benzooxazol-2-one (1equiv), 4-butylpiperidine (1 equiv), NaI (0.100 g, 0.67 mmol), and K₂CO₃(0.075 g, 0.54 mmol) in MeCN (1 ml) and shaken at 50° C. for 20 h. Thereaction mixture was cooled to r.t. and DCM was added (2 ml). Isocyanateresin (ca. 3 equiv, 1.1 mmol/g) was added and the mixture left at r.t.for 24 h. The mixture was filtered through cotton onto an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes) and concentrated in vacuo.

3.115 3-[2-(4-Butylpiperidin-1-yl)ethyl]-3H-benzothiazol-2-one (67KK20a)

3-(2-Chloroethyl)-3H-benzothiazol-2-one (62KK38) (0.043 g, 0.2 mmol) and4-butylpiperidine (0.028 g, 0.2 mmol) were reacted according to GP15 togive the title compound (67KK20a) (0.008 g, 13%). HPLC-MS (ammoniumacetate) [M+H]⁺=319.4.

3.116 3-[2-(2-Ethylpiperidin-1-yl)ethyl]-3H-benzothiazol-2-one (67KK17f)

3-(2-Chloroethyl)-3H-benzothiazol-2-one (62KK38) (0.032 g, 0.15 mmol)and 2-ethylpiperidine (0.017 g, 0.15 mmol) were reacted according toGP15 to give the title compound (67KK17f) (0.003 g, 7%). HPLC-MS(ammonium acetate) [M+H]⁺=291.3.

3.117 3-[2-(4-Methylpiperidin-1-yl)ethyl]-3H-benzothiazol-2-one(67KK20c)

3-(2-Chloroethyl)-3H-benzothiazol-2-one (62KK38) (0.043 g, 0.2 mmol) and4-methylpiperidine (0.020 g, 0.2 mmol) were reacted according to GP15 togive the title compound (67KK20c) (0.008 g, 14%). HPLC-MS (ammoniumacetate) [M+H]⁺=277.3.

3.118 3-[3-(4-Butylpiperidin-1-yl)propyl]-3H-benzothiazol-2-one(62KK40d)

3-(3-Chloropropyl)-3H-benzothiazol-2-one (62KK21) (0.046 g, 0.2 mmol)and 4-butylpiperidine (0.028 g, 0.2 mmol) were reacted according to GP15to give the title compound (62KK40d) (0.042 g, 63%). HPLC-MS (ammoniumacetate) [M+H]⁺=333.1.

3.119 3-[3-(2-Ethylpiperidin-1-yl)propyl]-3H-benzothiazol-2-one(67KK01f)

3-(3-Chloropropyl)-3H-benzothiazol-2-one (62KK21) (0.048 g, 0.21 mmol)and 2-ethylpiperidine (0.022 g, 0.19 mmol) were reacted according toGP15 to give the title compound (67KK01f) (0.015 g, 26%). HPLC-MS(ammonium acetate) [M+H]⁺=305.1.

3.120 3-[3-(4-Methylpiperidin-1-yl)propyl]-3H-benzothiazol-2-one(67KK01g)

3-(3-Chloropropyl)-3H-benzothiazol-2-one (62KK21) (0.048 g, 0.21 mmol)and 4-methylpiperidine (0.020 g, 0.20 mmol) were reacted according toGP15 to give the title compound (67KK01g) (0.024 g, 41%). HPLC-MS(ammonium acetate) [M+H]⁺=291.0.

3.121 3-[4-(4-Butylpiperidin-1-yl)butyl]-3H-benzothiazol-2-one (62KK40e)

3-(4-Chlorobutyl)-3H-benzothiazol-2-one (62KK29) (0.049 g, 0.20 mmol)and 4-butylpiperidine (0.028 g, 0.20 mmol) were reacted according toGP15 to give the title compound (62KK40e) (0.032 g, 46%). HPLC-MS(ammonium acetate) [M+H]⁺=347.1.

3.122 3-[4-(2-Ethylpiperidin-1-yl)butyl]-3H-benzothiazol-2-one (67KK04f)

3-(4-Chlorobutyl)-3H-benzothiazol-2-one (62KK29) (0.025 g, 0.10 mmol)and 2-ethylpiperidine (0.011 g, 0.10 mmol) were reacted according toGP15 to give the title compound (67KK04f) (0.015 g, 47%). HPLC-MS(ammonium acetate) [M+H]⁺=319.1.

3.123 3-[4-(4-Methylpiperidin-1-yl)butyl]-3H-benzothiazol-2-one(67KK40g)

3-(4-Chlorobutyl)-3H-benzothiazol-2-one (62KK29) (0.025 g, 0.10 mmol)and 4-methylpiperidine (0.010 g, 0.10 mmol) were reacted according toGP15 to give the title compound (67KK04g) (0.019 g, 62%). HPLC-MS(ammonium acetate) [M+H]⁺=305.1.

3.124 3-[2-(4-Butylpiperidin-1-yl)ethyl]-3H-benzooxazol-2-one (62KK40f)

3-(2-Chloroethyl)-3H-benzooxazol-2-one (62KK39) (0.039 g, 0.20 mmol) and4-butylpiperidine (0.028 g, 0.20 mmol) were reacted according to GP15 togive the title compound (62KK40f) (0.014 g, 23%). HPLC-MS (ammoniumacetate) [M+H]⁺=303.1.

3.125 3-[2-(2-Ethylpiperidin-1-yl)ethyl]-3H-benzooxazol-2-one (67KK16-f)

3-(2-Chloroethyl)-3H-benzooxazol-2-one (62KK39) (0.032 g, 0.16 mmol) and2-ethylpiperidine (0.017 g, 0.15 mmol) were reacted according to GP15 togive the title compound (67KK16-f) (0.006 g, 15%). HPLC-MS (ammoniumacetate) [M+H]⁺=275.4.

3.126 3-[2-(4-Methylpiperidin-1-yl)ethyl]-3H-benzooxazol-2-one(67KK16-g)

3-(2-Chloroethyl)-3H-benzooxazol-2-one (62KK39) (0.032 g, 0.16 mmol) and4-methylpiperidine (0.015 g, 0.15 mmol) were reacted according to GP15to give the title compound (67KK16-g) (0.015 g, 38%). HPLC-MS (ammoniumacetate) [M+H]⁺=261.3.

3.127 3-[3-(4-Butylpiperidin-1-yl)propyl]-3H-benzooxazol-2-one (62KK40g)

3-(3-Chloropropyl)-3H-benzooxazol-2-one (62KK30) (0.042 g, 0.20 mmol)and 4-butylpiperidine (0.028 g, 0.20 mmol) were reacted according toGP15 to give the title compound (62KK40g) (0.033 g, 52%). HPLC-MS(ammonium acetate) [M+H]⁺=317.3.

3.128 3-[3-(2-Ethylpiperidin-1-yl)propyl]-3H-benzooxazol-2-one(67KK07-f)

3-(3-Chloropropyl)-3H-benzooxazol-2-one (62KK30) (0.021 g, 0.10 mmol)and 2-ethylpiperidine (0.011 g, 0.10 mmol) were reacted according toGP15 to give the title compound (67KK07-f) (0.013 g, 45%). HPLC-MS(ammonium acetate) [M+H]⁺=289.1.

3.129 3-[3-(4-Methylpiperidin-1-yl)propyl]-3H-benzooxazol-2-one(67KK07-g)

3-(3-Chloropropyl)-3H-benzooxazol-2-one (62KK30) (0.021 g, 0.10 mmol)and 4-methylpiperidine (0.010 g, 0.10 mmol) were reacted according toGP15 to give the title compound (67KK07-g) (0.016 g, 58%). HPLC-MS(ammonium acetate) [M+H]⁺=275.1.

3.130 3-[4-(4-Butylpiperidin-1-yl)butyl]-3H-benzooxazol-2-one (62KK40h)

3-(4-Chlorobutyl)-3H-benzooxazol-2-one (62KK28) (0.045 g, 0.20 mmol) and4-butylpiperidine (0.028 g, 0.20 mmol) were reacted according to GP15 togive the title compound (62KK40h) (0.031 g, 47%). HPLC-MS (ammoniumacetate) [M+H]⁺=331.2.

3.131 3-[4-(2-Ethylpiperidin-1-yl)butyl]-3H-benzooxazol-2-one (67KK06-f)

3-(4-Chlorobutyl)-3H-benzooxazol-2-one (62KK28) (0.023 g, 0.10 mmol) and2-ethylpiperidine (0.011 g, 0.10 mmol) were reacted according to GP15 togive the title compound (67KK06-f) (0.007 g, 23%). HPLC-MS (ammoniumacetate) [M+H]⁺=303.1.

3.132 3-[4-(4-Methylpiperidin-1-yl)butyl]-3H-benzooxazol-2-one(67KK016-g)

3-(4-Chlorobutyl)-3H-benzooxazol-2-one (62KK28) (0.023 g, 0.10 mmol) and4-methylpiperidine (0.010 g, 0.10 mmol) were reacted according to GP15to give the title compound (67KK06-g) (0.009 g, 31%). HPLC-MS (ammoniumacetate) [M+H]⁺=289.1.

3.133 General Procedure 16 (GP16)

A 4 ml vial was charged with 3-(3-chloropropyl)-3H-benzooxazol-2-one (1equiv), 4-butylpiperidine (1.2 equiv), NaI (0.100 g, 0.67 mmol), andK₂CO₃ (0.075 g, 0.54 mmol) in MeCN (1 ml) and shaken at 50° C. for 20 h.The reaction mixture was cooled to r.t., water added (1 ml), and theproduct was extracted into EtOAc (2×1 ml). The combined org. layer wasadded an acidic ion-exchange column. The column was washed with MeOH (2column volumes) then the product was eluded of the column using 10%ammonium hydroxide in MeOH (2 column volumes) and concentrated in vacuo.The product was purified by flash CC and/or by prep. RP-HPLC[conditions: stationary phase, Luna 15 um C18; column, 250×21.2 mm;mobile phase, 20 ml/min, H₂O/MeCN, ammoniumacetate buffer (25 nM)].

3.134 3-[3-(4-butylpiperidin-1-yl]propyl)-4-methyl-3H-benzooxazol-2-one(86KK25a)

3-(3-Chloropropyl)-4-methyl-3H-benzooxazol-2-one (86KK21a) (0.063 g,0.28 mmol) and 4-butylpiperidine (0.044 g, 0.31 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK25a) (0.039 g, 42%). ¹H NMR (CD₃OD+CDCl₃) δ 0.87 (t, J=6.7 Hz,CH₃), 1.30-1.08 (m, 9H), 1.62 (d, J=11.9 Hz, 2H), 1.97-1.87 (m, 4H),2.42 (t. J=7.2 Hz, CH₂), 2.55 (s, CH₃), 2.86 (d, J=11.7 Hz, 2H), 4.03 (tJ=7.0, CH₂), 7.05-6.94 (m, 3H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.4, 17.6,23.8, 27.8, 30.0, 33.0, 36.7, 37.2, 43.0, 55.0, 56.8, 108.7, 121.5,123.4, 128.1, 129.9, 144.1, 156.8; HPLC-MS (ammonium acetate)[M+H]⁺=331.3 (MH⁺).

3.1353-[3-(4-butylpiperidin-1-yl]propyl)-5,7-dimethyl-3H-benzooxazol-2-one(86KK25b)

3-(3-Chloropropyl)-5,7-dimethyl-3H-benzooxazol-2-one (86KK21b) (0.043 g,0.18 mmol) and 4-butylpiperidine (0.028 g, 0.20 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK25b) (0.032 g, 52%). ¹H NMR (CD₃OD+CDCl₃) δ 0.88 (t, J=6.5 Hz,CH₃), 1.27-1.11 (m, 9H), 1.64 (d, J=12.1 Hz, 2H), 1.98-1.87 (m, 4H),2.30 (s, CH₃), 2.35 (s, CH₃), 2.39-2.35 (m, 2H), 2.84 (d, J=11.7 Hz,2H), 3.84 (t, J=6.7 Hz, CH₂), 6.75 (s, 1H), 6.81 (s, 1H); ¹³C NMR(CD₃OD+CDCl₃) δ 14.4, 14.4, 21.6, 23.8, 25.6, 29.9, 33.0, 36.6, 37.2,41.5, 54.9, 56.7, 107.9, 120.8, 125.5, 131.8, 134.9, 140.3, 156.6;HPLC-MS (ammonium acetate) [M+H]⁺=345.3.

3.136 3-[3-(4-butylpiperidin-1-yl]propyl)-6-methyl-3H-benzooxazol-2-one(86KK25c)

3-(3-chlorpropyl)-6-methyl-3H-benzooxazol-2-one (86KK21 c) (0.052 g,0.23 mmol) and 4-butylpiperidine (0.035 g, 0.25 mmol) were reactedaccording to GP16. Purified by prep. RP-HPCL to give the title compound(86KK25c) (0.014 g, 18%). ¹H NMR (CD₃OD+CDCl₃) δ 0.88 (t, J=7.0, CH₃),1.29-1.12 (m, 9H), 1.65 (d, J=11.1 Hz, 2H), 2.00-1.89 (m, 4H), 2.38 (s,CH₃), 2.41-2.38 (m, 2H), 2.86 (d, J=11.9 Hz, 2H), 3.87 (t, J=6.8, CH₂),7.06-7.04 (m, 3H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.4, 21.4, 23.7, 25.6, 29.9,32.9, 36.6, 37.1, 41.5, 54.8, 56.7, 109.5, 111.3, 125.4, 129.9, 133.9,143.9, 156.4; HPLC-MS (ammonium acetate) [M+H]⁺=331.3.

3.137 3-[3-(4-butylpiperidin-1-yl]propyl)-5-methyl-3H-benzooxazol-2-one(86KK25d)

3-(3-chloropropyl)-5-methyl-3H-benzooxazol-2-one (86KK21d) (0.032 g,0.14 mmol) and 4-butylpiperidine (0.021 g, 0.15 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK25d) (0.022 g, 48%). ¹H NMR (CD₃OD+CDCl₃) δ 0.89 (t, J=7.0, CH₃),1.29-1.15 (m, 9H), 1.64 (d, J=10.6, 2H), 1.98-1.67 (m, 4H), 2.37-2.41(m, 2H), 2.39 (s, CH₃), 2.86 (d, J=11.9 Hz, 2H), 3.87 (t, J=6.9, CH₂),6.92-7.09 (m, 3H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.4, 21.6, 23.8, 25.7, 29.9,33.0, 36.6, 37.2, 41.4, 54.9, 56.6, 110.3, 110.4, 123.9, 132.3, 135.2,141.9, 156.6; HPLC-MS (ammonium acetate) [M+H]⁺=331.3.

3.138 5-t-Butyl-3-[3-(4-butylpiperidin-1-yl)propyl]-3H-benzooxazol-2-one(86KK25e)

5-t-butyl-3-(3-chloropropyl)-3H-benzooxazol-2-one (86KK21e) (0.056 g,0.21 mmol) and 4-butylpiperidine (0.032 g, 0.23 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK25e) (0.103 g, 50%). ¹H NMR (CD₃OD+CDCl₃) δ 0.88 (t, J=6.6 Hz,CH₃), 1.34-1.11 (m, 18H), 1.63 (d, J=11.3 Hz, 2H), 1.88-1.99 (m, 4H),2.41 (t, J=7.2 Hz, CH₂), 2.86 (d, J=11.9 Hz, 2H), 3.91 (t, J=6.8 Hz,CH₂), 7.19-7.11 (m, 3H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.4, 23.7, 25.7, 29.9,32.0, 33.0, 35.7, 36.6, 37.1, 41.4, 54.9, 56.8, 107.0, 110.0, 120.4,132.0, 141.7, 148.9, 156.7; HPLC-MS (ammonium acetate) [M+H]⁺=373.3.

3.139 3-[3-(4-butylpiperidin-1-yl)propyl]-6-chloro-3H-benzooxazol-2-one(86KK25f)

3-(3-chloropropyl)-6-chloro-3H-benzooxazol-2-one (86KK21f) (0.138 g,0.56 mmol) and 4-butylpiperidine (0.088 g, 0.62 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK25f) (0.103 g, 53%). ¹H NMR (CD₃OD) δ 0.89 (t, J=6.9, CH₃),1.31-1.08 (m, 9H), 1.62 (d, J=11.9, 2H), 1.84-1.98 (m, 4H), 2.38 (t,J=7.0 Hz, CH₂), 2.83 (d, J=11.9 Hz, 2H), 3.89 (t, J=6.7 Hz, CH₂),7.28-7.17 (m, 3H); ¹³C NMR (CD₃OD) δ 14.4, 23.9, 25.6, 30.1, 33.1, 36.8,37.4, 41.9, 55.0, 56.8, 110.9, 111.5, 125.1, 128.7, 131.6, 144.3, 155.9;HPLC-MS (ammonium acetate) [M+H]⁺=351.2.

3.140 3-[3-(4-butylpiperidin-1-yl)propyl]-5-methoxy-3H-benzooxazol-2-one(86KK22i)

3-(3-chloropropyl)-5-methoxy-3H-benzooxazol-2-one (86KK21i) (0.041 g,0.17 mmol) and 4-butylpiperidine (0.027 g, 0.19 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK22i) (0.103 g, 36%). ¹H NMR (CD₃OD+CDCl₃) δ 0.88 (t, J=6.9 Hz,CH₃), 1.28-1.13 (m, 9H), 1.65 (d, J=12.1 Hz, 2H), 1.98-1.89 (m, 4H),2.39 (t, J=7.2 Hz, CH₂), 2.86 (d, J=11.9 Hz, 2H), 3.81 (s, OCH₃), 3.86(t, J=6.9 Hz, CH₂), 6.67-6.65 (m, 1H), 6.77-6.76 (m, 1H), 7.11-7.09 (m,1H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.3, 23.7, 25.6, 29.8, 32.9, 36.5, 37.1,41.4, 54.8, 56.4, 56.6, 96.9, 108.1, 110.9, 132.9, 137.7, 156.8, 158.1;HPLC-MS (ammonium acetate) [M+H]⁺=347.1.

3.141 3-[3-(4-butylpiperidin-1-yl)propyl]-5-fluoro-3H-benzooxazol-2-one(86KK22k)

3-(3-chloropropyl)-5-fluoro-3H-benzooxazol-2-one (86KK21k) (0.039 g,0.17 mmol) and 4-butylpiperidine (0.027 g, 0.19 mmol) were reactedaccording to GP16. Purified by prep. RP-HPLC to give the title compound(86KK22k) (0.032 g, 56%). ¹H NMR (CD₃OD) δ 0.89 (t, J=7.0 Hz, CH₃),1.29-1.09 (m, 9H), 1.64 (, J=11.9 Hz, 2H), 1.99-1.86 (m, 4H), 2.38 (t,J=7.0 Hz, CH₂), 2.84 (d, J=11.7 Hz, CH₂), 3.89 (t, J=6.8 Hz, CH₂),6.88-6.83 (m, 1H), 7.22-7.09 (m, 2H); ¹³C NMR (CD₃OD) δ 14.4, 23.9,25.5, 30.1, 33.2, 36.8, 37.4, 41.9, 55.0, 56.8, 98.6 (J=30.3 Hz), 109.4(J=25.2 Hz), 111.4 (J=9.7 Hz), 133.7 (J=13.2 Hz), 140.0 (J=2.3 Hz),156.7, 161.1 (J=240.0 Hz); HPLC-MS (ammonium acetate) [M+H]⁺=335.1

3.142 3-[3-(4-butylpiperidin-1-yl)propyl]-6-fluoro-3H-benzooxazol-2-one(97KK28)

3-(3-chloropropyl)-6-fluoro-3H-benzooxazol-2-one (86KK21j) (0.090 g,0.39 mmol) and 4-butylpiperidine (0.070 g, 0.50 mmol) were reactedaccording to GP16. Purified by flash CC (SiO₂; DCM/MeOH 20:1) and prep.RP-HPLC to give the title compound (97KK28) (0.065 g, 50%). ¹H NMR(CD₃OD) δ 0.89 (t, J=7.0, CH₃), 1.29-1.09 (m, 9H), 1.64 (d, J=11.7,CH₂), 1.99-1.86 (m, 4H), 2.38 (t, J=7.0 Hz, CH₂), 2.84 (d, J=11.9 Hz,2H), 3.90 (t, J=6.9 Hz, CH₂), 7.02-6.96 (m, 1H), 7.21-7.10 (m, 2H); ¹³CCD₃OD) δ 14.4, 23.9, 25.6, 30.1, 33.2, 36.8, 37.4, 41.8, 55.0, 56.9,99.9 (J=29.4 Hz), 110.4 (J=9.4 Hz), 111.4 (J=24.2 Hz), 129.0 (J=1.9 Hz),144.1 (J=13.6 Hz), 156.4, 160.2 (J=240.0 Hz); HPLC-MS (ammonium acetate)[M+H]⁺=335.3

3.143 General Procedure 17 (GP17)

A 4 ml vial was charged with 3-(3-bromopropyl)-3H-benzooxazol-2-one (1equiv), 4-butylpiperidine (1.4 equiv), and K₂CO₃ (0.075 g, 0.54 mmol) inMeCN (1 ml) and shaken at 60° C. for 20 h. The reaction mixture wascooled to r.t., water was added (1 ml), and the product extracted intoethyl acetate (2×1 ml). The combined org. layer was added an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes). The product was purified by flash CC and/orby prep. RP-HPLC [conditions: stationary phase, Luna 15 um C18; column,250×21.2 mm; mobile phase, 20 ml/min, H₂O/MeCN, ammoniumacetate buffer(25 nM)].

3.144 3-[3-(4-butylpiperidin-1-yl)propyl]-6-methoxy-3H-benzooxazol-2-one(97KK02a)

3-(3-Bromopropyl)-6-methoxy-3H-benzooxazol-2-one (97KK01a) (0.093 g,0.56 mmol) and 4-butylpiperidine (0.086 g, 0.61 mmol) were reactedaccording to GP17. Purified by prep. RP-HPLC to give the title compound(97KK02a) (0.114 g, 71%). ¹H NMR (CD₃OD) δ 0.89 (t, J=6.1 Hz, CH₃),1.27-1.12 (m, 9H), 1.64 (d, J=11.7 Hz, 2H), 1.99-1.88 (m, 4H), 2.39 (t,J=7.2 Hz, CH₂), 2.86 (d, J=11.5 Hz, 2H), 3.78 (s, OCH₃), 3.86 (t, J=6.6Hz, CH₂), 7.10-6.78 (m, 3H); ¹³C NMR (CD₃OD) δ 14.4, 23.9, 25.7, 30.1,33.1, 36.8, 37.4, 41.6, 55.0, 56.5, 56.9, 98.3, 126.0, 144.7, 156.7,157.8; HPLC-MS (ammonium acetate) [M+H]⁺=347.3.

3.1453-[3-(4-butylpiperidin-1-yl)propyl]-5,7-dibromo-3H-benzooxazol-2-one(97KK02b)

3-(3-Bromopropyl)-5,7-dibromo-3H-benzooxazol-2-one (97KK02b) (0.138 g,0.47 mmol) and 4-butylpiperidine (0.069 g, 0.49 mmol) were reactedaccording to GP17. Purified by prep. RP-HPLC to give the title compound(97KK02b) (0.152 g, 78%). ¹H NMR (CD₃OD+CDCl₃) δ 0.80 (t, J=6.6 Hz,CH₃), 1.18-1.06 (m, 9H), 1.61 (d, J=12.1 Hz, 2H), 1.95-1.89 (m, 4H),2.38 (t, J=6.6 Hz, CH₂), 2.81 (d, J=11.7 Hz, 2H), 3.81 (t, J=6.6 Hz,CH₂), 7.34-7.28 (m, 2H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.3, 23.4, 24.8, 29.6,32.4, 36.0, 36.7, 41.7, 54.4, 55.8, 103.5, 112.1, 117.6, 128.4, 134.0,140.7, 154.5; HPLC-MS (ammonium acetate) [M+H]⁺=473.0.

3.146 3-[3-(4-butylpiperidin-1-yl)propyl]-7-methyl-3H-benzooxazol-2-one(97KK06a)

Crude 3-(3-bromopropyl)-7-methyl-3H-benzooxazol-2-one (97KK03a) (0.074g) and 4-butylpiperidine (0.052 g, 0.37 mmol) were reacted according toGP17. Purified by prep. RP-HPLC to give the title compound (97KK06a)(0.056 g). ¹H NMR (CD₃OD+CDCl₃) δ 0.87 (t, J=6.1 Hz, CH₃), 1.26-1.17 (m,9H), 1.68 (d, J=12.1 Hz, 2H), 2.10-1.97 (m, 4H), 2.34 (s, CH₃), 2.53 (t,J=7.4 Hz, CH₂), 2.96 (d, J=11.3 Hz, 2H), 3.88 (t, J=6.8 Hz), 6.97-6.93(m, 2H), 7.11-7.08 (m, 1H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.3, 14.4, 23.6,23.8, 25.1, 29.7, 32.2, 36.0, 36.8, 41.2, 54.5, 56.2, 107.1, 121.2,124.7, 125.0, 131.6, 142.1, 156.1; HPLC-MS (ammonium acetate)[M+H]⁺=331.3.

3.1473-[3-(4-butylpiperidin-1-yl)propyl]-7-isopropyl-3H-benzooxazol-2-one(97KK06b)

Crude 3-(3-bromopropyl)-7-isopropyl-3H-benzooxazol-2-one (97KK03b)(0.059 g) and 4-butylpiperidine (0.039 g, 0.28 mmol) were reactedaccording to GP17. Purified by prep. RP-HPLC. Purified by prep. RP-HPLCto give the title compound (97KK06b) (0.044 g). ¹H NMR (CD₃OD) δ 0.88(t, J=6.3 Hz, CH₃), 1.32-1.07 (m, 15H), 1.61 (d, J=12.1 Hz, 2H),1.99-1.84 (m, 4H), 2.39 (t, J=7.0 Hz, CH₂), 2.83 (d, J=11.3 Hz, 2H),3.19 (sept, J=6.8 Hz, CH), 3.89 (t, J=6.7 Hz, CH₂), 7.03-7.00 (m, 2H),7.17-7.13 (M, 1H); ¹³C NMR (CD₃OD) δ 14.4, 22.8, 23.9, 25.7, 29.9, 30.1,33.2, 36.9, 37.4, 41.8, 55.0, 57.0, 107.7, 121.3, 125.2, 132.3, 132.3,141.4, 156.5; HPLC-MS (ammonium acetate) [M+H]⁺=359.3.

3.1483-[3-(4-butylpiperidin-1-yl)propyl]-5,7-diisopropyl-3H-benzooxazol-2-one(97KK07a)

Crude 3-(3-bromopropyl)-5,7-diisopropyl-3H-benzooxazol-2-one (97KK03c)(0.077 g) and 4-butylpiperidine (0.040 g, 0.28 mmol) were reactedaccording to GP17. Purified by prep. RP-HPLC to give the title compound(97KK07a) (0.056 g). ¹H NMR (CD₃OD) δ 0.88 (m, CH₃), 1.32-1.16 (m, 21H),1.69 (d, J=12.1, 2H), 2.17-2.01 (m, 4H), 2.60 (t, J=7.2, CH₂), 3.03-2.92(m, 3H), 3.15 (sept, J=6.9 Hz, CH), 3.90 (t, J=6.7 Hz, CH₂), 6.88 (s,1H), 6.92 (s, 1H); ¹³C NMR (CD₃OD) δ 14.4, 22.8, 23.9, 24.8, 25.3, 30.0,30.3, 32.5, 35.8, 36.3, 37.1, 41.3, 54.7, 56.5, 105.6, 119.5, 132.0,132.3, 139.7, 146.9, 156.8; HPLC-MS (ammonium acetate) [M+H]⁺=401.4.

3.1493-[3-(4-butylpiperidin-1-yl)propyl]-4,6-dimethoxy-3H-benzooxazol-2-one(97KK07c)

3-(3-Bromopropyl)-4,6-dimethoxy-3H-benzooxazol-2-one (97KK05b) (0.033 g,0.10 mmol) and 4-butylpiperidine (0.024 g, 0.17 mmol) were reactedaccording to GP17. Purified by prep. RP-HPLC to give the title compound(97KK07c) (0.023 g, 61%). ¹H NMR (CD₃OD) δ 0.89 (m, CH₃), 1.27-1.13 (m,9H), 1.66 (d, J=11.9 Hz, 2H), 2.03-1.95 (m, 4H), 2.47 (t, J=6.8 Hz,CH₂), 2.94 (d, J=10.6 Hz, 2H), 3.78 (s, OCH₃), 3.90 (s, OCH₃), 3.96 (t,J=6.8 Hz, CH₂), 6.54-6.46 (m, 2H); ¹³C NMR (CD₃OD) δ 14.4, 23.8, 24.1,29.9, 30.2, 35.0, 36.3, 53.8, 53.9, 54.1, 56.5, 115.3, 125.0, 129.6,130.6, 131.1, 159.3, 161.1; HPLC-MS (ammonium acetate) [M+H]⁺=377.3.

3.150 3-[3-(4-Butylpiperidin-1-yl)propyl]7-fluoro-3H-benzooxazol-2-one(97KK13)

3-(3-bromopropyl)-7-fluoro-3H-benzooxazol-2-one (97KK12a) (0.100 g, 0.36mmol) and 4-butylpiperidine (0.095 g, 0.67 mmol) were reacted accordingto GP17. Purified by flash CC (SiO₂; DCM/MeOH 10:1) and prep. RP-HPLC togive the title compound (97KK13) (0.078 g, 65%). ¹H NMR (CD₃OD) δ 0.88(t, J=6.9 Hz, CH₃), 1.29-1.07 (m, 9H), 1.61 (d, J=11.9 Hz, 2H),1.99-1.84 (m, 4H), 2.39 (t, J=7.0 Hz, CH₂), 2.83 (d, J=11.7 Hz, 2H),3.91 (t, J=6.8 Hz, CH₂), 6.97-6.92 (m, 1H), 7.06-7.03 (m, 1H), 7.22-7.17(m, 1H); ¹³C NMR (CD₃OD) δ 14.4, 23.9, 25.5, 30.0, 33.1, 36.8, 37.4,42.3, 55.0, 56.9, 106.3 (J=3.9 Hz), 111.0 (J=17.1 Hz), 125.8 (J=6.8 Hz),130.7 (J=14.2 Hz), 135.3 (J=4.8 Hz), 147.1 (J=247.4), 155.6; HPLC-MS(ammonium acetate) [M+H]⁺=335.3.

3.1513-[3-(4-Butylpiperidin-1-yl)propyl]-5,7-dichloro-6-methyl-3H-benzooxazol-2-one(97KK16)

Crude 3-(3-bromopropyl)-5,7-dichloro-6-methyl-3H-benzooxazol-2-one(97KK12b) (0.051 g) and 4-butylpiperidine (0.041 g, 0.29 mmol) werereacted according to GP17. Purified by prep. RP-HPLC to give the titlecompound (97KK16) (0.016 g). ¹H NMR (CD₃OD+CDCl₃) δ 0.88 (t, J=6.6 Hz,CH₃), 1.29-1.07 (m, 9H), 1.63 (d, J=12.1 Hz, 2H), 1.97-1.87 (m, 4H),2.38 (t, J=7.2 Hz, CH₂), 2.44 (s, CH₃), 2.83 (d, J=11.7 Hz, 2H), 3.87(t, J=6.7 Hz, CH₂), 7.27 (s, 1H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.4, 16.7,23.8, 25.2, 29.9, 32.9, 36.5, 37.2, 42.0, 54.8, 56.4, 109.5, 117.0,129.0, 130.8, 131.7, 139.5, 155.2; HPLC-MS (ammonium acetate)[M+H]⁺=399.2.

3.152 General Procedure 18 (GP18)

A 4 ml vial was charged with 3H-benzooxazol-2-one (1 equiv),3-(4-butylpiperidin-1-yl)propan-1-ol (1.2 equiv), diethylazodicarboxylate (1.2 equiv), and triphenylphosphine (1.2 equiv) in THF(4 ml) and shaken at r.t. for 20 h. The reaction mixture was added water(1 ml), and the product extracted into EtOAc (2×1 ml). The combined org.layer was added an acidic ion-exchange column. The column was washedwith MeOH (2 column volumes) then the product was eluded of the columnusing 10% ammonium hydroxide in MeOH (2 column volumes). The product waspurified by flash CC and/or by prep. RP-HPLC [conditions: stationaryphase, Luna 15 um C18; column, 250×21.2 mm; mobile phase, 20 ml/min,H₂O/MeCN, ammoniumacetate buffer (25 nM)].

3.153 3-(4-Butylpiperidin-1-yl)propan-1-ol (92LH52)

A vial was charged with 4-butylpiperidine (0.706 g, 5.0 mmol),3-bromopropan-1-ol (0.694 g, 5.0 mmol), and K₂CO₃ (0.967 g, 7.0 mmol) inMeCN (4 ml) and was shaken at 50° for 72 h. The reaction mixture wasadded water and the product was extracted into EtOAc. The combined org.layer was dried over Na₂SO₄ and concentrated in vacuo. The material wasused for the next reaction step without further purification.

3.1543-[3-(4-butylpiperidin-1-yl)propyl]-5,7-dichloro-6-ethyl-3H-benzooxazol-2-one(97KK14)

5,7-Dichloro-6-ethyl-3H-benzooxazol-2-one (97KK10) (0.257 g, 1.11 mmol),3-(4-butylpiperidin-1yl)propan-1-ol (0.272 g, 1.36 mmol), diethylazodicarboxylate (0.232 g, 1.33 mmol), and PPh₃ (0.355 g, 1.35 mmol) inTHF (4 ml) were reacted according to GP18. Purified by flash CC (SiO₂;DCM/MeOH 20:1) and prep. RP-HPLC to give the title compound (97KK14)(0.058 g, 13%). ¹H NMR (CD₃OD+CDCl₃) δ 0.87 (t, J=6.6 Hz, CH₃),1.28-1.04 (m, 12H), 1.61 (d, J=11.9 Hz, 2H, 1.95-1.85 (m, 4H), 2.38 (t,J=7.0 Hz, CH₂), 2.81 (d, J=11.7 Hz, 2H), 2.93 (q, J=7.4 Hz, CH₂), 3.87(t, J=6.6 Hz, CH₂), 7.23 (s, 1H); ¹³C NMR (CD₃OD+CDCl₃) δ 13.2, 14.4,23.6, 24.8, 25.1, 29.8, 32.8, 36.4, 37.1, 42.0, 54.7, 56.3, 109.6,116.6, 130.2, 131.6, 134.5, 139.4, 155.1.

3.1555-Bromo-3-[3-(4-butylpiperidin-1-yl)propyl]-7-fluoro-3H-benzooxazol-2-one(97KK15-a)

5-Bromo-7-fluoro-3H-benzooxazol-2-one (97KK09b) (0.049 g, 0.21 mmol),3-(4-butylpiperidin-1yl)propan-1-ol (0.066 g, 0.33 mmol), diethylazodicarboxylate (0.044 g, 0.25 mmol), and PPh₃ (0.071 g, 0.27 mmol) inTHF (2 ml) were reacted according to GP18. Purified by flash CC (SiO₂;DCM/MeOH 20:1) and prep. RP-HPLC to give the title compound (97KK15-a)(0.019 g, 22%). ¹H NMR (CD₃OD+CDCl₃) δ 0.80 (t, J=6.8 Hz, CH₃),1.23-1.04 (m, 9H), 1.58 (d J=13.3 Hz, 2H), 1.90-1.81 (m, 4H), 2.30 (t,J=7.0 Hz, CH₂), 2.76 (d, J=11.7 Hz, 2H), 3.81 (t, J=6.7 Hz, CH₂),7.20-7.06 (m, 2H); HPLC-MS (ammonium acetate) [M+H]⁺=413.2.

3.1563-[3-(Butylpiperidin-1-yl)propyl]-6,7-difluoro-3H-benzooxazol-2-one(97KK15-b)

6,7-Difluoro-3H-benzooxazol-2-one (97KK11) (0.136 g, 0.79 mmol),3-(4-butylpiperidin-1yl)propan-1-ol (0.196 g, 0.98 mmol), diethylazodicarboxylate (0.165 g, 0.95 mmol), and PPh₃ (0.389 g, 1.48 mmol) inTHF (2 ml) was reacted according to GP18. Purified by flash CC (SiO₂;DCM/MeOH 20:1) and prep. RP-HPLC to give the title compound (97KK15-b)(0.063 g, 23%). ¹H NMR (CD₃OD) δ 0.89 (m, CH₃), 1.31-1.05 (m, 9H), 1.64(d, J=12.5 Hz, 2H), 2.00-1.87 (m, 4H), 2.42 (t, J=7.2, CH₂), 2.86 (d,J=11.7 Hz, 2H), 3.91 (t, J=6.6 Hz, CH₂), 7.03-6.99 (m, 1H), 7.17-7.10(m, 1H); ¹³C NMR (CD₃OD) δ 14.4, 23.9, 25.3, 30.0, 33.0, 36.7, 37.3,42.2, 55.0, 56.8, 105.0 (J=4.6 Hz, J=7.7 Hz), 112.7 (J=20.4 Hz), 130.7,131.8 (J=4.6 Hz, J=10.8 Hz), 136.8 (J=18.5 Hz, J=251.4 Hz), 148.3(J=10.0, J=240.6 Hz), 155.6; HPLC-MS (ammonium acetate) [M+H]⁺=353.3.

3.1573-[3-(Butylpiperidin-1-yl)propyl]-4,5,7-trichloro-3H-benzooxazol-2-one(97KK29)

4,5,7-Trichloro-3H-benzooxazol-2-one (97KK26) (0.342 g, 1.43 mmol),3-(4-butylpiperidin-1yl)propan-1-ol (0.280 g, 1.40 mmol), diethylazodicarboxylate (0.299 g, 1.72 mmol), and PPh₃ (0.516 g, 1.97 mmol) inTHF (5 ml) was reacted according to GP18. Purified by flash CC (SiO₂;DCM/MeOH 20:1) and prep. RP-HPLC to give the title compound (97KK29)(0.085 g, 14%). ¹H NMR (CD₃OD+CDCl₃) δ 0.88 (t, J=6.7 Hz, CH₃),1.29-0.90 (m, 9H), 1.65 (d, J=13.5 Hz, 2H), 2.11-1.89 (m, 4H), 2.62 (t,J=7.0 Hz, CH₂), 2.96 (d, J=11.9 Hz, 2H), 4.23 (t, J=6.8 Hz, CH₂), 7.40(s, 1H); ¹³C NMR (CD₃OD+CDCl₃) δ 14.3, 23.8, 26.8, 29.8, 32.4, 36.1,37.0, 43.4, 54.7, 56.5, 113.6, 115.4, 124.4, 130.1, 131.3, 140.0, 155.1;HPLC-MS (ammonium acetate) [M+H]⁺=419.1.

3.158 3-[3-(4-butylpiperidin-1-yl)propyl]-4-methoxy-3H-benzooxazol-2-one(92LH60-1A)

A 4 ml vial was charged with 4-methoxy-3H-benzooxazol-2-one (92LH58)(0.345 g, 0.73 mmol), 3-(4-butylpiperidin-1-yl)propan-1-ol (0.175 g,0.88 mmol), diethyl azodicarboxylate (0.152 g, 0.88 mmol), andtriphenylphosphine (0.230 g, 0.88 mmol) in THF (4 ml) and shaken at r.t.for 20 h. The reaction mixture was added was added an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes). The product was purified by flash CC (SiO₂;EtOAc) and by prep. RP-HPLC [conditions: stationary phase, Luna 15 umC18; column, 250×21.2 mm; mobile phase, 20 ml/min, H₂O/MeCN,ammoniumacetate buffer (25 nM)] to give the title compound (92LH60-1A)(0.135 g, 53%). ¹H NMR (CD₃OD) δ 0.88 (t J=6.8 Hz, CH₃), 1.28-1.06 (m,9H), 1.60 (d, J=10.9 Hz, 2H), 1.99-1.82 (m, 4H), 2.38 (t, J=7.0 Hz,CH₂), 2.84 (d, J=11.9 Hz, 2H), 3.92 (s, OCH₃), 3.98 (t, J=6.8 Hz, CH₂),6.86-6.81 (m, 2H), 7.07-7.03 (m, 1H); ¹³C NMR (CD₃OD) δ 13.2, 23.7,27.2, 29.8, 32.9, 36.6, 37.1, 43.5, 54.8, 56.5, 56.8, 103.8, 108.3,120.1, 123.8, 144.6, 146.3, 156.0; HPLC-MS (ammonium acetate)[M+H]⁺=347.

3.159 3-[3-(4-butylpiperidin-1-yl)propyl]-7-nitro-3H-benzooxazol-2-one(92LH60-2A)

A 4 ml vial was charged with 7-nitro-3H-benzooxazol-2-one (92LH59)(0.090 g, 0.5 mmol), 3-(4-butylpiperidin-1-yl)propan-1-ol (0.120 g, 0.60mmol), diethyl azodicarboxylate (0.153 g, 0.60 mmol), andtriphenylphosphine (0.230 g, 0.60 mmol) in THF (4 ml) and shaken at r.t.for 20 h. The reaction mixture was added was added an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes). The product was purified by flash CC (SiO₂;EtOAc) and by prep. RP-HPLC [conditions: stationary phase, Luna 15 umC18; column, 250×21.2 mm; mobile phase, 20 ml/min, H₂O/MeCN,ammoniumacetate buffer (25 nM)] to give the title compound (92LH60-2A(0.067 g, 37%). ¹H NMR (CD₃OD) δ 0.88 (t, J=6.6 Hz, CH₃), 1.60-0.98 (m,9H), 1.81 (d, J=12.7 Hz, 2H), 2.01-1.84 (m, 4H), 2.41 (t, J=7.0 Hz,CH₂), 2.80 (d, J=11.7 Hz, 2H), 4.00 (t, J=6.8 Hz, CH₂), 7.42-7.38 (m,1H), 7.62-7.59 (m, 1H), 7.90-7.88 (m, 1H); HPLC-MS (ammonium acetate)[M+H]⁺=362.

3.1603-[3-(4-butylpiperidin-1-yl)propyl]-5,7-diiodo-3H-benzooxazol-2-one(92LH66)

A 4 ml vial was charged with 5,7-diiodo-3H-benzooxazol-2-one (92LH49)(0.166 g, 0.40 mmol), 3-(4-butylpiperidin-1-yl)propan-1-ol (0.096 g,0.48 mmol), diethyl azodicarboxylate (0.084 g, 0.48 mmol), andtriphenylphosphine (0.126 g, 0.48 mmol) in THF (4 ml) and shaken at r.t.for 20 h. The reaction mixture was added was added an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes). The product was purified prep. RP-HPLC[conditions: stationary phase, Luna 15 um C18; column, 250×21.2 mm;mobile phase, 20 ml/min, H₂O/MeCN, ammoniumacetate buffer (25 nM)] togive the title compound (92LH66) (0.068 g, 30%). ¹H NMR (CD₃OD) δ 0.80(t, J=7.0 Hz, CH₃), 1.20-1.12 (m, 9H), 1.53 (d, J=13.1 Hz, 2H),1.91-1.80 (m, 4H), 2.33 (t, J=7.0 Hz, CH₂), 2.76 (d, J=11.7 Hz, 2H),3.78 (t, J=6.5 Hz, CH₂), 7.68-7.47 (m, 2H); ¹³C NMR (CD₃OD) δ 14.4,23.9, 25.0, 30.1, 33.1, 36.7, 37.4, 42.2, 55.0, 56.6, 74.6, 87.8, 118.9,133.9, 139.6, 145.6, 154.7; HPLC-MS (ammonium acetate) [M+H]⁺=569.

3.1613-[3-(4-butylpiperidin-1-yl)propyl]-4-methyl-7-isopropyl-3H-benzooxazol-2-one(92LH75)

A 4 ml vial was charged with 4-methyl-7-isopropyl-3H-benzooxazol-2-one(92LH71) (0.100 g, 0.52 mmol), 3-(4-butylpiperidin-1-yl)propan-1-ol(0.124 g, 0.62 mmol), diethyl azodicarboxylate (0.109 g, 0.62 mmol), andtriphenylphosphine (0.164 g, 0.62 mmol) in THF (4 ml) and shaken at r.t.for 20 h. The reaction mixture was added was added an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes). The product was purified by prep. RP-HPLC[conditions: stationary phase, Luna 15 um C18; column, 250×21.2 mm;mobile phase, 20 ml/min, H₂O/MeCN, ammoniumacetate buffer (25 nM)] togive the title compound (92LH75) (0.100 g, 52%). ¹H NMR (CD₃OD) δ 0.90(m, CH₃), 1.33-1.21 (m, 15H), 1.76 (d, J=13.5 Hz, 2H), 2.08 (quint, 7.8Hz, CH₂), 2.40-2.34 (m, 2H), 2.53 (s, CH₃), 2.82-2.78 (m, 2H), 3.19-3.14(m, 3H), 4.08 (t, J=6.9 Hz, CH₂), 6.94-6.90 (m, 2H); ¹³C NMR (CD₃OD) δ14.4, 17.4, 22.7, 23.8, 27.0, 29.4, 29.9, 31.9, 35.8, 36.9, 42.4, 54.5,56.1, 119.0, 121.1, 128.2, 129.6, 130.0, 141.6, 157.0; HPLC-MS (ammoniumacetate) [M+H]⁺=373.

3.1623-[3-(4-butylpiperidin-1-yl)propyl]-7-methyl-4-isopropyl-3H-benzooxazol-2-one(92LH77)

A 4 ml vial was charged with 7-methyl-4-isopropyl-3H-benzooxazol-2-one(92LH76) (0.066 g, 0.35 mmol), 3-(4-butylpiperidin-1-yl)propan-1-ol(0.084 g, 0.42 mmol), diethyl azodicarboxylate (0.073 g, 0.42 mmol), andtriphenylphosphine (0.110 g, 0.42 mmol) in THF (4 ml) and shaken at r.t.for 20 h. The reaction mixture was added was added an acidicion-exchange column. The column was washed with MeOH (2 column volumes)then the product was eluded of the column using 10% ammonium hydroxidein MeOH (2 column volumes). The product was purified by prep. RP-HPLC[conditions: stationary phase, Luna 15 um C18; column, 250×21.2 mm;mobile phase, 20 ml/min, H₂O/MeCN, ammoniumacetate buffer (25 nM)] togive the title compound (92LH77) (0.035 g, 27%). ¹H NMR (CD₃OD) δ 0.90(t, J=6.3 Hz, CH₃), 1.33-1.13 (m, 15H), 1.68 (d, J=12.7 Hz, 2H),2.11-1.94 (m, 4H), 2.30 (s, CH₃), 2.58 (t, J=7.2 Hz, CH₂), 2.98 (d,J=11.5 Hz, 2H), 3.36-3.31 (m, 1H), 4.07 (t, J=7.0 Hz, CH₂), 7.10-6.93(m, 2H); ¹³C NMR (CD₃OD) δ 14.2, 14.4, 23.9, 24.4, 26.9, 28.1, 30.0,32.7, 36.4, 37.2, 43.5, 55.0, 56.7, 118.8, 122.4, 125.5, 127.8, 130.6,142.6, 157.3; HPLC-MS (ammonium acetate) [M+H]⁺=373.

3.163 General Procedure 19 (GP19)

A 4 ml vial was charged with 3-chloroalkyl-3H-benzothiazol-2-one (1equiv), piperidine (1 equiv), KI (1.3 equiv), and K₂CO₃ (1.3 equiv) inMeCN (2 ml) and shaken at 50° C. for 48 h. The reaction mixture wasadded water, the product extracted into EtOAc, and the combined org.layer was concentrated. The product was purified by flash CC (SiO₂;EtOAC, MeOH/EtOAc 1:4).

3.164 3-[5-(4-Butylpiperidin-1-yl)pentyl)-3H-benzothiazol-2-one(107LH03-1)

3-(5-Chloropentyl)-3H-benzothiazol-2-one (107LH01) (0.203 g, 0.9 mmol),4-butylpiperidine (0.127 g, 0.9 mmol), KI (0.200 g, 1.2 mmol), and K₂CO₃(0.166 g, 1.2 mmol) in MeCN (2 ml) were reacted according to GP19.Purified by flash CC (SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the titlecompound (107LH03-1) (0.173 g, 53%). ¹H NMR (CD₃OD) δ 0.88 (m, CH₃),1.38-1.19 (m, 11H), 1.76-1.50 (m, 6H), 1.94-1.89 (m, 2H), 2.28 (t, J=7.4Hz, CH₂), 2.88 (d, J=10.8 Hz, 2H), 3.96 (t, J=7.0 Hz, CH₂), 7.23-7.14(m, 2H), 7.36-7.32 (m, 1H), 7.48-7.46 (m, 1H); ¹³C NMR (CD₃OD) δ 14.5,23.9, 25.7, 27.0, 28.5, 30.1, 32.9, 36.7, 37.3, 43.5, 54.9, 59.8, 112.3,123.5, 123.7, 124.3, 127.7, 138.4, 171.4; HPLC-MS (ammonium acetate)[M+H]⁺=361.3.

3.165 3-[5-(4-Propyloxypiperidin-1-yl)pentyl)-3H-benzothiazol-2-one(107LH03-2)

3-(5-Chloropentyl)-3H-benzothiazol-2-one (107LH01) (0.203 g, 0.9 mmol),4-propyloxypiperidine (0.129 g, 0.9 mmol), KI (0.200 g, 1.2 mmol), andK₂CO₃ (0.166 g, 1.2 mmol) in MeCN (2 ml) were reacted according to GP19.Purified by flash CC (SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the titlecompound (107LH03-2) (0.153 g, 47%). ¹H NMR (CD₃OD) δ 0.90 (t, J=7.4 Hz,CH₃), 1.61-1.30(m, 9H), 1.76-1.69 (m, 2H), 1.90-1.84 (m, 2H), 2.23-2.18(m, 2H), 2.35-2.31 (m, 2H), 2.76-2.74 (m, 2H), 3.39-3.29 (m, 2H), 3.95(t, J=7.2 Hz, CH₂), 7.22-7.14 (m, 2H), 7.36-7.32 (m, 1H), 7.48-7.46 (m,1H); ¹³C NMR (CD₃OD) δ 11.0, 24.2, 25.6, 27.0, 28.4, 31.6, 43.5, 51.9,59.2, 70.6, 112.3, 123.5, 123.7, 124.4, 127.7, 138.4, 171.5; HPLC-MS(ammonium acetate) [M+H]⁺=363.3.

3.166 3-[6-(4-Butylpiperidin-1-yl)hexyl)-3H-benzothiazol-2-one(107LH04-1)

3-(6-Chlorohexyl)-3H-benzothiazol-2-one (107LH02) (0.243 g, 0.9 mmol),4-butylpiperidine (0.127 g, 0.9 mmol), KI (0.200 g, 1.2 mmol), and K₂CO₃(0.166 g, 1.2 mmol) in MeCN (2 ml) were reacted according to GP19.Purified by flash CC (SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the titlecompound (107LH04-1) (0.186 g, 55%). ¹H NMR (CD₃OD) δ 0.88 (m, CH₃),1.47-1.19 (m, 15H), 1.72-1.63 (m, 4H), 1.94-1.89 (m, 2H), 2.28 (t, J=7.4Hz, CH₂), 2.88 (d, J=11.0 Hz, 2H), 3.94 (t, J=7.0 Hz, CH₂), 7.21-7.15(m, 2H), 7.35-7.31 (m, 1H), 7.47-7.45 (m, 1H); ¹³C NMR (CD₃OD) δ 14.5,23.9, 27.2, 27.5, 28.3, 28.5, 30.1, 32.9, 36.7, 37.3, 43.6, 54.9, 59.9,112.3, 123.5, 123.7, 124.3, 127.7, 138.4, 171.4; HPLC-MS (ammoniumacetate) [M+H]⁺=375.3.

3.167 3-[6-(4-Propyloxypiperidin-1-yl)hexyl)-3H-benzothiazol-2-one(107LH04-2)

3-(6-Chlorohexyl)-3H-benzothiazol-2-one (107LH02) (0.243 g, 0.9 mmol),4-propyloxypiperidine (0.129 g, 0.9 mmol), KI (0.200 g, 1.2 mmol), andK₂CO₃ (0.166 g, 1.2 mmol) in MeCN (2 ml) were reacted according to GP19.Purified by flash CC (SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the titlecompound (107LH04-1) (0.159 g, 47%). ¹H NMR (CD₃OD) δ 0.90 (t, J=7.4 Hz,CH₃), 1.89-1.34 (m, 15H), 2.32-2.17 (m, 4H), 2.73 (br. s, 2H), 3.39-3.30(m, 2H), 3.94 (t, J=6.7 Hz, CH₂), 7.22-7.14 (m, 2H), 7.35-7.32 (m, 1H),7.48-7.46 (m, 1H); ¹³C NMR (CD₃OD) δ 11.1, 24.3, 27.3, 27.5, 28.2, 28.5,31.7, 43.5, 51.9, 59.4, 70.6, 112.3, 123.5, 123.7, 124.3, 127.7, 138.4,171.4; HPLC-MS (ammonium acetate) [M+H]⁺=377.3.

3.168 General Procedure 20 (GP20)

A 7 ml vial was charged with1-(3-chloropropyl)-1,3-dihydrobenzoimidazol-2-one (210 mg, 1.0 mmol),amine (0.5 mmol), NaI (150 mg, 1.0 mmol), sodium carbonate (106 mg, 1.0mmol) and MeCN (2 ml) and shaken at 60° C. for 18 h. The reaction wascooled to r.t. and water (1 ml) was added. The product was extractedinto ethyl acetate (2×1 ml) and the organic layer loaded onto a VarianSCX ion exchange column. The column was washed with MeOH (2 columnvolumes) then the product was eluted off the column using 10% ammoniumhydroxide in MeOH (2 column volumes). The solute was concentrated invacuo, dissolved up in acetone, dried (K₂CO₃) and concentrated in vacuobefore being purified further.

3.1691-{3-[4-(2-Hydroxyethyl)piperidin-1-yl]propyl}-1,3-dihydrobenzoimidazol-2-one)(45NK-55)

The reaction was carried out according to the GP20 using2-piperidin-4-ylethanol (65 mg, 0.5 mmol). The product was purifiedusing an Isco CombiFlash Sq 16× (4.1 g silica column, eluting DCM (5min), 0-20% MeOH in DCM (20 min), 20% MeOH in DCM (15 min)). MeOH (2 ml)and HCl in ether (2 M, 0.2 ml) were added, the solution concentrated togive the title compound (45NK-55) as the hydrochloride salt (4 mg). ¹HNMR (CD₃OD) δ 1.44 (m, 2H), 1.52 (q, 2H), 1.74 (m, 1H), 1.95 (br. d,2H), 2.17 (m, 2H), 2.86 (br. t, 2H), 3.08 (m, 2H), 3.45 (br. d, 2H),3.61 (t, 2H), 4.01 (t, 2H), 7.14 (m, 3H), 7.19 (m, 1H); LC-MS [M+H]⁺304.2.

3.1701-[3-(3,5-Dimethylpiperidin-1-yl)propyl]-1,3-dihydrobenzoimidazol-2-one(45NK-56)

The reaction was carried out according to the GP20 using3,5-dimethylpiperidine (57 mg, 0.5 mmol). MeOH (2 ml) and HCl in ether(2 M, 0.2 ml) were added, the solution concentrated and the productrecrystallised from MeOH-ether to give the title compound (45NK-56) asthe hydrochloride salt (17 mg). ¹H NMR (CD₃OD) δ 0.95 (d, 1H), 0.97 (d,4H), 1.21 (d, 1H), 1.41 (dt, 0.67H), 1.67 (br. d, 0.67H), 1.83-1.97 (m,2H), 2.11 (m, 0.33H), 2.22 (m, 2H), 2.47 (m, 2H), 3.00 (dd, 09.33H),3.17 (m, 2H), 3.36-3.45 (m, 2H), 3.96-4.08 (m, 2H), 7.16 (m, 3H), 7.21(m, 1H); LC-MS [M+H]⁺ 288.3 (2 peaks).

3.1711-[3-(4-Methylpiperidin-1-yl)propyl]-1,3-dihydrobenzoimidazol-2-one(45NK-58)

The reaction was carried out according to the GP20 using4-methylpiperidine (50 mg, 0.5 mmol). The product was purified using anIsco CombiFlash Sq 16× (4.1 g silica column, eluting DCM (5 min), 0-15%MeOH in DCM (20 min), 15% MeOH in DCM (15 min)). MeOH (2 ml) and HCl inether (2 M, 0.2 ml) were added, the solution concentrated to give thetitle compound (45NK-58) as the hydrochloride salt (24 mg). ¹H NMR(CDCl₃) δ 0.93 (d, 3H), 1.54 (m, 1H), 1.62-1.75 (m, 4H), 2.28 (tt, 2H),2.53 (br. t, 2H), 2.94 (dd, 2H), 3.31 (br. d, 2H), 3.94 (t, 2H), 6.99(m, 3H), 7.09 (m, 1H), 10.2 (br. s, 1H); LC-MS [M+H]⁺ 274.2.

3.1721-[3-(4-(Hydroxymethyl)piperidin-1-yl)propyl]-1,3-dihydrobenzoimidazol-2-one(45NK-60)

The reaction was carried out according to the GP20 usingpiperidin-4-ylMeOH (58 mg, 0.5 mmol). The product was purified using anIsco CombiFlash Sq 16× (4.1 g silica column, eluting DCM (5 min), 0-15%MeOH in DCM (20 min), 15% MeOH in DCM (15 min)). MeOH (2 ml) and HCl inether (2 M, 0.2 ml) were added, the solution concentrated to give thetitle compound (45NK-60) as the hydrochloride salt (28 mg). ¹H NMR(CD₃OD) δ 1.46 (dq, 2H), 1.69 (m, 1H), 1.92 (br. d, 2H), 2.16 (tt, 2H),2.76 (br. t, 2H), 3.01 (dd, 2H), 3.40 (m, 2H), 3.43 (d, 2H), 4.00 (t,2H), 7.08 (m, 3H), 7.20 (m, 1H); LC-MS [M+H]⁺ 290.2.

3.1731-{3-[4-(3-Methylbutylidene)piperidin-1-yl]propyl}-1,3-dihydrobenzoimidazol-2-one(45NK70)

The reaction was carried out according to the GP20 using4-(3-methylbutylidene)piperidine hydrochloride (95 mg, 0.5 mmol). Theproduct was purified using an Isco CombiFlash Sq 16× (4.1 g silicacolumn, eluting DCM (5 min), 0-15% MeOH in DCM (20 min), 15% MeOH in DCM(15 min)). MeOH (2 ml) and HCl in ether (2 M, 0.2 ml) were added, thesolution concentrated to give the title compound (45NK70) as thehydrochloride salt (10 mg). ¹H NMR (CD₃OD) δ 0.86 (d, 6H), 1.55 (sept,1H), 1.86 (t, 2H), 1.96 (tt, 2H), 2.18 (t, 2H), 2.22 (t, 2H), 2.40 (m,6H), 3.93 (t, 2H), 5.15 (t, 1H), 7.06 (m, 3H), 7.16 (m, 1H); ¹³C NMR(CD₃OD) δ 22.7, 26.6, 28.8, 30.1, 36.6, 37.2, 39.9, 55.7, 56.6, 109.3,110.4, 122.4, 122.7, 123.0, 129.6, 131.6, 137.1, 156.9; LC-MS [M+H]⁺328.

3.1741-[3-(4-Pentylpiperidin-1-yl)propyl]-1,3-dihydrobenzoimidazol-2-one(45NK71)

The reaction was carried out according to the GP20 using4-pentylpiperidine hydrochloride trifluoroacetate (199 mg, 0.5 mmol).The product was purified using an Isco CombiFlash Sq 16× (4.1 g silicacolumn, eluting DCM (5 min), 0-15% MeOH in DCM (20 min), 15% MeOH in DCM(15 min)). MeOH (2 ml) and HCl in ether (2 M, 0.2 ml) were added, thesolution concentrated to give the title compound (45NK71) as thehydrochloride salt (4 mg). ¹H NMR (CD₃OD) δ 0.88 (t, 3H), 1.14-1.35 (m,11H), 1.66 (br. d, 2H), 1.95 (m, 4H), 2.42 (dd, 2H), 2.90 (br. d, 2H),3.92 (t, 2H), 7.06 (m, 3H), 7.18 (m, 1H); LC-MS [M+H]⁺ 330.3.

3.1751-[3-(4-Butylpiperidin-1-yl)propyl]-3-methyl-1,3-dihydrobenzoimidazol-2-one(45NK110)

1-(3-Chloro-propyl)-3-methyl-1,3-dihydro-benzoimidazol-2-one (450 mg,2.0 mmol), 4-butyl-piperidine (282 mg, 2.0 mmol), NaI (300 mg, 2.0 mmol)and sodium carbonate (212 mg, 2.0 mmol) were shaken in MeCN (5 ml) at80° C. for 18 h. The reaction was cooled to r.t., water (5 ml) was addedand the product extracted with ethyl acetate (2×20 ml). The organiclayer was dried (K₂CO₃), filtered and concentrated in vacuo before beingpurified by using an Isco CombiFlash Sq 16× (10 g silica column, eluting0-15% MeOH in DCM (33 min) then 15% MeOH in DCM (13 min)) to give thetitle compound (45NK110) (50 mg). The hydrochloride salt was formed byaddition of HCl (4M in dioxane) and recrystallised from MeOH-Et₂O togive a white precipitate which was filtered and dried. ¹H NMR (CD₃OD) δ0.91 (t, 3H), 1.31 (m, 6H), 1.44 (m, 2H), 1.54 (m, 1H), 1.95 (br. s,2H), 2.22 (m, 2H), 2.92 (br. t, 2H), 3.15 (m, 2H), 3.43 (s, 3H), 3.55(m, 2H), 4.04 (t, 2H), 7.17 (m, 3H), 7.23 (m, 1H); m.p. 157.7-158.4° C.

3.176 General Procedure 21 (GP21)

The amine (0.10 mmol) in DCM (0.3 ml) and iodide (0.12 mmol) in DMF (0.2ml) were added to a reaction vessel and DCM (1 ml) was added. Thereactions were shaken at r.t. for 72 h then isocyanate resin (ca. 50 mg,1.1 mmol/g) was added and the reactions were shaken at r.t. for 24 h.The reactions were filtered, washing with MeOH (1 ml) onto a SCX ionexchange column which had been prewashed with MeOH (2 column volumes).The column was washed with MeOH (2 column volumes) then the product waseluted off the column using 5% aqueous NH₃ in MeOH (1 column volume) andconcentrated in vacuo. The product was purified by the general prep.LC-MS procedure and the desired fractions were concentrated in vacuo togive the desired product.

3.1771-(4-[4-Cyclohexylmethyl-piperidin-1-yl]butyl)-1,3-dihydrobenzimidazol-2-one(56NK118B-cpd2)

4-(1-Cyclohexylmethyl)piperidine (18 mg, 0.10 mmol) and1-(4-iodobutyl)-1,3-dihydrobenzoimidazol-2-one (38 mg, 0.12 mmol) wereused according to general GP21 to give the trifluoroacetate salt of thetitle compound (56NK118-cpd2) (1.5 mg). HPLC-MS (ammonium acetate)[M+H]⁺=370.5.

3.1781-(3-[4-Cyclohexylmethyl-piperidin-1-yl]propyl)-1,3-dihydrobenzimidazol-2-one(56NK138-A1)

4-(1-Cyclohexylmethyl)piperidine (18 mg, 0.10 mmol) and1-(3-iodopropyl)-1,3-dihydrobenzoimidazol-2-one (36 mg, 0.12 mmol) wereused according to GP21 to give the trifluoroacetate salt of the titlecompound (56NK138-A1) (3.1 mg). HPLC-MS (ammonium acetate) [M+H]⁺=356.5.

3.1791-(3-[4-(2-Ethoxyethyl)piperidin-1-yl]propyl)-1,3-dihydrobenzimidazol-2-one(56NK138-A2)

4-(2-Ethoxyethyl)piperidine (16 mg, 0.10 mmol) and1-(3-iodopropyl)-1,3-dihydrobenzoimidazol-2-one (36 mg, 0.12 mmol) wereused according to GP21 to give the trifluoroacetate salt of the titlecompound (56NK138-A2) (3.7 mg). HPLC-MS (ammonium acetate) [M+H]⁺=332.4.

3.1801-(3-[4-Cyclohexylmethyl-piperidin-1-yl]propyl)-3-methyl-1,3-dihydrobenzimidazol-2-one(56NK138-B1)

4-(1-Cyclohexylmethyl)piperidine (18 mg, 0.10 mmol) and1-(3-iodopropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (38 mg, 0.12mmol) were used according to GP21 to give the trifluoroacetate salt ofthe title compound (56NK138-B1) (1.3 mg). HPLC-MS (ammonium acetate)[M+H]⁺=370.5.

3.1811-(3-[4-(2-Ethoxyethyl)piperidin-1-yl]propyl)-3-methyl-1,3-dihydrobenzimidazol-2-one(56NK138-B2)

4-(2-Ethoxyethyl)piperidine (16 mg, 0.10 mmol) and1-(3-iodopropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (38 mg, 0.12mmol) were used according to GP21 to give the trifluoroacetate salt ofthe title compound (56NK138-B2) (7.3 mg). HPLC-MS (ammonium acetate)[M+H]⁺=346.5.

3.1823-(3-[4-Cyclohexylmethyl-piperidin-1-yl]propyl)-3H-benzothiazol-2-one(56NK138-C1)

4-(1-Cyclohexylmethyl)piperidine (18 mg, 0.10 mmol) and1-(3-iodopropyl)-3H-benzothiazol-2-one (38 mg, 0.12 mmol) were usedaccording to GP21 to give the trifluoroacetate salt of the titlecompound (56NK138-C1) (2.2 mg). HPLC-MS (ammonium acetate) [M+H]⁺=373.4.

3.1833-(3-[4-(2-Ethoxyethyl)piperidin-1-yl]propyl)-3H-benzothiazol-2-one(56NK138-C2)

4-(2-Ethoxyethyl)piperidine (16 mg, 0.10 mmol) and1-(3-iodopropyl)-3H-benzothiazol-2-one (38 mg, 0.12 mmol) were usedaccording to GP21 to give the trifluoroacetate salt of the titlecompound (56NK138-C2) (2.5 mg). HPLC-MS (ammonium acetate) [M+H]⁺=349.4.

3.1841-(3-[4-Allyloxy-piperidin-1-yl]propyl)-1,3-dihydrobenzimidazol-2-one(56NK136-A4)

4-(1-Cyclohexylmethyl)piperidine (18 mg, 0.10 mmol) and1-(3-iodopropyl)-1,3-dihydrobenzoimidazol-2-one (36 mg, 0.12 mmol) wereused according to GP21 to give the trifluoroacetate salt of the titlecompound (56NK136-A4) (10.8 mg). ¹H NMR (CDCl₃) δ 8.17 (br. s, 1H),7.03-7.26 (m, 4H), 5.93 (ap. ddd, J=17.2, 10.4, 5.5 Hz, 1H), 5.26 (ap.ddd, J=17.2, 3.2, 1.6 Hz, 1H), 5.15 (ap. ddd, J=10.4, 2.8, 1.4 Hz, 1H),3.99 (ap. dt, J=5.5, 1.7 Hz, 2H), 3.93 (t, J=6.8 Hz, 2H), 3.35 (m, 1H),2.73 (m, 2H), 2.39 (t, J=7.1 Hz, 2H), 2.10 (m, 2H), 1.95 (tt, J=7.1,6.8, 2H), 1.90 (m, 2H), 1.63 (m, 2H); HPLC-MS (ammonium acetate)[M+H]⁺=316.40.

3.1851-(3-[4-Allyloxy-piperidin-1-yl]propyl)-3-methyl-1,3-dihydrobenzimidazol-2-one(56NK136-B4)

4-(2-Ethoxyethyl)piperidine (16 mg, 0.10 mmol) and1-(3-iodopropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (38 mg, 0.12mmol) were used according to GP21 to give the trifluoroacetate salt ofthe title compound (56NK136-B4) (8.3 mg). ¹H NMR (CDCl₃) δ 7.07 (m, 3H),6.97 (m, 1H), 5.93 (ap. ddd, J=17.2, 10.4, 5.5 Hz, 1H), 5.27 (ap. ddd,J=17.2, 3.2, 1.7 Hz, 1H), 5.15 (ap. ddd, J=10.4, 3.0, 1.8 Hz, 1H), 3.99(ap. dt, J=5.5, 1.7 Hz, 2H), 3.94 (t, J=6.9 Hz, 2H), 3.42 (s, 3H), 3.36(m, 1H), 2.72 (m, 2H), 2.39 (m, 2H), 2.10 (m, 2H), 1.92 (m, 4H), 1.61(m, 2H); HPLC-MS (ammonium acetate) [M+H]⁺=330.4.

3.186 General Procedure 22 (GP22)

The amine (0.10 mmol) in DCM (0.3 ml) and iodide (0.12 mmol) in DMF (0.2ml) were added to a reaction vessel and DCM (1 ml) was added. Thereactions were shaken at r.t. for 72 h then isocyanate resin (ca. 50 mg,1.1 mmol/g) was added and the reactions were shaken at r.t. for 24 h.The reactions were filtered, washing with MeOH (1 ml) onto a SCX ionexchange column which had been prewashed with MeOH (2 column volumes).The column was washed with MeOH (2 column volumes) then the product waseluted off the column using 5% aqueous NH₃ in MeOH (1 column volume) andconcentrated in vacuo. The product was purified by the general prep.LC-MS procedure and the desired fractions were made pH 12 by addition ofsodium hydroxide (2M). The product was extracted with EtOAc (3×5 ml),and the organic layer washed with brine (5 ml), dried (K₂CO₃) andconcentrated in vacuo to give the desired compound.

3.1871-(3-[4-Methyl-piperidin-1-yl]propyl)-3-methyl-1,3-dihydrobenzimidazol-2-one(56NK125-A)

4-Methylpiperidine (10 mg, 0.10 mmol) and1-(3-iodopropyl)-3-methyl-1,3-dihydrobenzoimidazol-2-one (38 mg, 0.12mmol) were used according to GP22 to give the title compound (56NK125-A)(8.4 mg). ¹H NMR (CDCl₃) δ 7.07 (m, 3H), 6.96 (m, 1H), 3.94 (t, J=7.0Hz, 2H), 3.41 (s, 3H), 2.84 (m, 2H), 2.37 (m, 2H), 1.93 (m, 4H), 1.61(m, 2H), 1.34 (m, 1H), 1.24 (m, 2H), 0.92 (d, J=6.2 Hz, 3H); HPLC-MS(ammonium acetate) [M+H]⁺=288.4.

3.188 1-[2-(4-Butylpiperidin-1-yl)ethyl]-1,3-dihydrobenzoimidazol-2-one(56NK117-A)

4-Butylpiperidine (14 mg, 0.10 mmol) and1-(2-iodoethyl)-1,3-dihydrobenzoimidazol-2-one (35 mg, 0.12 mmol) wereused according to GP22 to give the title compound (56NK117-A) (7.6 mg).HPLC-MS (ammonium acetate) [M+H]⁺=302.4.

3.189 1-[4-(4-Butylpiperidin-1-yl)butyl]-1,3-dihydrobenzoimidazol-2-one(56NK118-A)

4-Butylpiperidine (14 mg, 0.10 mmol) and1-(4-iodobutyl)-1,3-dihydrobenzoimidazol-2-one (38 mg, 0.12 mmol) wereused according to GP22 to give the title compound (56NK118-A) (11.6 mg).¹H NMR (CDCl₃) δ 9.02 (br. s, 1H), 7.06 (m, 3H), 7.01 (m, 1H), 3.90 (t,J=7.0 Hz, 2H), 2.89 (m, 2H), 2.37 (m, 2H), 1.89 (m, 2H), 1.79 (m, 2H),1.64 (m, 4H), 1.23 (m, 9H), 0.88 (m, 3H); HPLC-MS (ammonium acetate)[M+H]⁺=330.4.

3.190 3-[4-(4-Butylpiperidin-1-yl)butyl]-3H-benzooxazole-2-thione(56NK139C1)

3-(4-Chlorobutyl)-3H-benzooxazole-2-thione (68 mg, 0.28 mmol) and NaI(210 mg, 1.4 mmol) in acetone (10 ml) were heated to 50° C. for 72 hthen cooled to r.t. Aqueous sodium thiosulphate solution (10 ml) wasadded and the product was extracted into EtOAc (2×20 ml). The organiclayer was dried (K₂CO₃), filtered and concentrated in vacuo. DMF (0.2ml), DCM (1 ml) and 4-butylpiperidine (14 mg, 0.1 mmol) in acetonitile(0.2 ml) were added and the reaction was shaken at r.t. for 72 h thenisocyanate resin (ca. 50 mg, 1.1 mmol/g) was added and the reactionswere shaken at r.t. for 24 h. The reactions were filtered, washing withMeOH (1 ml) onto a SCX ion exchange column which had been prewashed withMeOH (2 column volumes). The column was washed with MeOH (2 columnvolumes) then the product was eluted off the column using 5% aqueous NH₃in MeOH (1 column volume) and concentrated in vacuo. The product waspurified by preparative LC/MS (method TJ1) and the desired fractionswere concentrated in vacuo to give the trifluoroacetate salt of thetitle compound (56NK139C1) (0.4 mg). HPLC-MS (ammonium acetate)[M+H]⁺=347.4.

3.1911-(3-[4-Cyclohexylpiperidin-1-yl]propyl)-1,3-dihydrobenzimidazol-2-one(75NK58-A2)

4-Cyclohexylpiperidine (33 mg, 0.20 mmol) in DCM (0.5 ml) and MeCN (0.5ml) was added to 1-(3-iodopropyl)-1,3-dihydrobenzoimidazol-2-one (76 mg,0.24 mmol), K₂CO₃ (66 mg, 0.48 mmol) and NaI (72 mg, 0.48 mmol). Thereaction was stirred at r.t. for 36 h then aqueous sodium thiosulphatesolution (5 ml) was added. The product was extracted into EtOAc (2×10ml), and the organic layer was dried (K₂CO₃), filtered and concentratedin vacuo. MeOH (1 ml) was added and the compound was loaded onto a SCXion exchange column which had been prewashed with MeOH (2 columnvolumes). The column was washed with MeOH (2 column volumes) then theproduct was eluted off the column using 5% aqueous NH₃ in MeOH (1 columnvolume) and concentrated in vacuo. The product was purified bypreparative LC/MS (method TJ1) and the desired fractions were made pH 12by addition of sodium hydroxide (2M). The product was extracted withEtOAc (3×5 ml), and the organic layer washed with brine (5 ml), dried(K₂CO₃) and concentrated in vacuo to give the title compound (75NK58-A2)(12.1 mg). ¹H NMR (CDCl₃) δ 9.25 (br. s, 1H), 7.07 (m, 4H), 3.93 (t,J=7.0 Hz, 2H), 2.93 (m, 2H), 2.40 (m, 2H), 1.98 (pent, J=7.0 Hz, 2H),1.86 (m, 2H), 1.69 (m, 7H), 1.32-0.87 (m, 9H); HPLC-MS (ammoniumacetate) [M+H]⁺=342.3.

3.192 1-(3-[4-Cyclohexylpiperidin-1-yl]propyl)-3H-benzothiazol-2-one(75NK58-B2)

4-Cyclohexylpiperidine (33 mg, 0.20 mmol) in DCM (0.5 ml) and MeCN (0.5ml) was added to 1-(3-iodopropyl)-3H-benzothiazol-2-one (77 mg, 0.24mmol), K₂CO₃ (66 mg, 0.48 mmol) and NaI (72 mg, 0.48 mmol). The reactionwas stirred at r.t. for 36 h then aqueous sodium thiosulphate solution(5 ml) was added. The product was extracted into EtOAc (2×10 ml), andthe organic layer was dried (K₂CO₃), filtered and concentrated in vacuo.MeOH (1 ml) was added and the compound was loaded onto a SCX ionexchange column which had been prewashed with MeOH (2 column volumes).The column was washed with MeOH (2 column volumes) then the product waseluted off the column using 5% aqueous NH₃ in MeOH (1 column volume) andconcentrated in vacuo. The product was purified by preparative LC/MS(method TJ1) and the desired fractions were made pH 12 by addition ofsodium hydroxide (2M). The product was extracted with EtOAc (3×5 ml),and the organic layer washed with brine (5 ml), dried (K₂CO₃) andconcentrated in vacuo to give the title compound (75NK58-B2) (9.1 mg).HPLC-MS (ammonium acetate) [M+H]⁺=359.2.

3.193 1-(3-(4-Butylpiperidin-1-yl)propyl)-1H-indol-2,3-dione (85LM03c)

A 50 ml flask, charged with 4-butylpiperidine (0.042 g, 0.30 mmol),1-(3-iodopropyl)-1H-indol-2,3-dione (85LM05) (0.113 g, 0.36 mmol) andK₂CO₃ (0.062 g, 0.45 mmol) in CH₃CN (20 ml), was stirred at 50° C. for24 hours. Water (10 ml) and EtOAc (10 ml) were added and the phases wereseparated. The water phase was re-extracted with EtOAc (10 ml). Thecombined organic phases were dried (Na₂SO₄) and evaporated to dryness.The crude product was purified by column chromatography (SiO₂;EtOAc/n-heptane 1:1+1% Et₃N) to give the title compound (85LM03c) (0.012g, 10%). ¹H NMR (CDCl₃) δ 0.95 (t, 3H), 1.10-1.30 (m, 8H), 1.60 (d, 2H),1.75-1.80 (m, 1H), 1.85-1.95 (m, 4H), 2.40 (t, 2H), 2.80 (d, 2H), 3.80(t, 2H), 7.0 (d, 1H), 7.10 (t, 1H), 7.55-7.65 (m, 2H); HPLC-MS (ammoniumacetate) [M+H]⁺=329.3.

3.194 1-(3-(4-Butylpiperidin-1-yl)propyl)-1,3-dihydro-indol-2-one(85LM12)

A mixture of compound1-(3-(4-Butyl-piperidin-1-yl)-propyl)-1H-indol-2,3-dione (85LM03c)(0.030 g, 0.09 mmol) and 10% Pd/C catalyst (0.016 g) in acetic acid (1.4ml) containing 70% perchloric acid (0.014 ml) was hydrogenated at 50° C.for 20 hours. After removal of the catalyst (filtration of the solutionthrough celite and wash with ethanol) the solution was evaporated. Water(10 ml) and EtOAc (10 ml) were added to the residue followed by additionof sodium hydroxide (1-2 drops) until pH 7. The EtOAc phase wasseparated, dried (Na₂SO₄) and evaporated to dryness. The crude productwas purified by column chromatography (SiO₂; EtOAc/n-heptane 1:3+1%Et₃N) to give the title compound (85LM12) (0.001 g, 4%). ¹H NMR (CDCl₃)δ 0.95 (t, 3H), 1.10-1.30 (m, 8H), 1.60 (d, 2H), 1.75-1.80 (m, 1H),1.85-1.95 (m, 4H), 2.40 (t, 2H), 2.80 (d, 2H), 3.48 (s, 2H), 3.80 (t,2H), 6.90-6.95 (m, 1H), 7.00-7.05 (m, 1H), 7.20-7.30 (m, 2H); HPLC-MS(ammonium acetate) [M+H]⁺=314.3.

3.195 3-(3-(4-Butylpiperidin-1-yl)propyl)-1H-indole (85LM18)

A 100 ml flask, charged with 4-butylpiperidine (1.7 g, 12.0 mmol), crudetoluene-4-sulfonic acid 3-(1H-indol-3-yl)-propyl ester (85LM17) (4.0 g)and K₂CO₃ (2.0 g, 14.4 mmol) in CH₃CN (20 ml), was stirred at 50° C. for24 hours. Water (20 ml) and EtOAc (20 ml) were added and the phases wereseparated. The aqueous phase was re-extracted with EtOAc (20 ml). Thecombined organic phases were dried (Na₂SO₄) and evaporated to dryness.The crude product was purified by column chromatography (SiO₂;EtOAc/n-heptane 1:3) to give the title compound (85LM18) (0.8 g, 10%-3steps). ¹H NMR (CDCl₃) δ 0.95 (t, 3H), 1.18-1.38 (m, 8H), 1.65 (d, 3H),1.83-1.98 (m, 4H), 2.40 (t, 2H), 2.78 (t, 2H), 2.90 (d, 2H), 6.98 (s,1H), 7.10 (t, 1H), 7.20 (t, 1H), 7.35 (d, 1H), 7.62 (d, 1H); HPLC-MS(ammunium acetate) [M+H]⁺=299.3.

3.196 3-(3-(4-Butylpiperidin-1-yl]propyl)-1,3-dihydro-indol-2-one(85LM23)

3-(3-(4-Butylpiperidin-1-yl)propyl)-1H-indole (85LM18) (0.156 g, 0.52)was dissolved in DMSO (1 ml) in a 10 ml flask and stirred at roomtemperature. Concentrated hydrochloric acid (0.04 ml, 0.52 mmol) wasadded slowly and stirring was continued for 24 hours. Water (10 ml) wasadded and then aqueous sodium bicarbonate (10-20 ml) until pH 7 followedby extraction with EtOAc (2×20 ml). The combined organic phases weredried (Na₂SO₄) and evaporated to dryness. The crude product was purifiedby column chromatography (SiO₂; EtOAc/n-heptane 1:10) and prep. RP-HPLC(conditions: stationary phase, Luna 15 um C18; column, 250×21.2 mm;mobile phase, 20 ml/min, H₂O/CH₃CN, ammoniumacetate buffer (25 nM)) togive the title compound (85LM23) (0.002 g, 1%). ¹H NMR (CDCl₃) δ 0.95(t, 3H), 1.10-1.30 (m, 8H), 1.50-1.70 (m, 5H), 1.80-1.90 (m, 2H),1.90-2.00 (m, 2H), 2.30 (m, 2H), 2.85 (m, 2H), 3.45 (m, 2H), 6.80 (d,1H), 7.00 (t, 1H), 7.20-7.30 (m, 2H); HPLC-MS (ammonium acetate)[M+H]⁺=315.3.

3.197 General Procedure 23 (GP23)

A 7 ml sealed vial, charged with 4-propoxy-piperidine (1 equiv),chloroalkylheterocycle (1 equiv), NaI (2 equiv) and K₂CO₃ (equiv) inMeCN (4 ml), was stirred at 50° C. for 24 hours. The mixture was pouredinto water (20 ml) followed by extraction with EtOAc (2×20 ml). Thecombined organic phases were dried (Na₂SO₄) and evaporated to dryness.The crude product was purified by column chromatography (SiO₂; MeOH/DCM1:20).

3.198 3-(3-(4-Propoxypiperidine-1-yl)-propyl)-3H-benzooxazol-2-one(85LM37)

3-(3-Chloropropyl)-3H-benzooxazol-2-one (62KK30) (0.200 G, 0.95 mmol),4-propoxypiperidine (0.138 g, 0.95 mmol), NaI (0.285 g, 1.90 mmol), andK₂CO₃ (0.262 g, 1.90 mmol) were reacted according to GP23 to give thetitle compound (85LM37) (0.21 μg, 70%). ¹H NMR (CDCl₃) δ 0.95 (t, 3H),1.50-1.65 (m, 4H), 1.80-1.90 (m, 2H), 1.95-2.00 (m, 2H), 2.00-2.10 (m,2H), 2.40 (t, 2H), 2.65-2.75 (m, 2H), 3.20-3.30 (m, 1H), 3.40 (t, 2H),3.90 (t, 2H), 7.05-7.15 (m, 2H), 7.15-7.25 (m, 2H); HPLC-MS (ammoniumacetate) [M+H]⁺=319.3.

3.1991-(3-(4-Butylpiperidine-1-yl)propyl)-1,3-dihydro-benzimidazol-2-one(85LM35)

1-(3-chloropropyl)-1,3-dihydro-benzimidazol-2-one (0.200 G, 0.95 mmol),4-propoxypiperidine (0.138 g, 0.95 mmol), NaI (0.285 g, 1.90 mmol), andK₂CO₃ (0.262 g, 1.90 mmol) were reacted according to GP23 to give thetitle compound (85LM35) (0.183 g, 60%). ¹H NMR (CD₃OD) δ 0.95 (t, 3H),1.50-1.65 (m, 2H), 1.75-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.15 (m, 2H),2.85-3.00 (m, 4H), 3.10-3.20 (m, 2H), 3.40 (t, 2H), 3.55 (m, 1H), 4.00(t, 2H), 7.05-7.15 (m, 3H), 7.20 (d, 1H); HPLC-MS (ammonium acetate)[M+H]⁺=318.3.

3.2003-(3-(4-Butyl-piperidin-1-yl)-2-hydroxy-propyl)-3H-benzothiazol-2-one(85LM15)

A 50 ml flask, charged with 4-butylpiperidine (0.152 g, 1.1 mmol), crude3-(3-bromo-2-hydroxypropyl)-3H-benzothiazol-2-one (85LM04) (0.308 g) andK₂CO₃ (0.295 g, 2.1 mmol) in MeCN (10 ml), was stirred at 50° C. for 24hours. Water (10 ml) and EtOAc (10 ml) were added and the phases wereseparated. The aqueous phase was re-extracted with EtOAc (10 ml). Thecombined organic phases were dried (Na₂SO₄) and evaporated to dryness.The crude product was purified by column chromatography (SiO₂;EtOAc/n-heptane 1:3) to give the title compound (85LM15) (0.261 g, 28%-2steps). ¹H NMR (CDCl₃) δ 0.90-1.0 (m, 6H), 1.15-1.30 (m, 9H), 1.60-1.70(m, 2H), 1.90 (t, 1H), 2.25 (t, 1H), 2.40 (m, 1H), 2.05 (dd, 1H), 2.75(d, 1H), 2.90 (d, 1H), 3.90 (dd, 1H), 4.00-4.15 (m, 2H), 7.10-7.20 (m,1H), 7.25-4.05 (m, 3H); HPLC-MS (ammonium acetate) [M+H]⁺=349.1.

3.201 General Procedure 24 (GP24)

A 100 ml flask, charged with piperidine (1 equiv),3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one (85LM13) (1.2 equiv),NaI (2 equiv) and K₂CO₃ (2 equiv) in MeCN (30 ml), was stirred at 100°C. for 5 days. Water (20 ml) and EtOAc (20 ml) were added and the phaseswere separated. The aqueous phase was re-extracted with EtOAc (20 ml).The combined organic phases were dried (Na₂SO₄) and evaporated todryness. The crude product was purified by column chromatography (SiO₂;EtOAc/n-heptane 1:3).

3.2023-(3-(4-Butyl-piperidin-1-yl)-2-methyl-propyl)-3H-benzothiazol-2-one(85LM14)

4-Butylpiperidine (0.471 g, 3.3 mmol),3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one (0.964 g, 4.0 mmol),NaI (1.0 g, 6.7 mmol), and K₂CO₃ (0.93 g, 6.7 mmol) were reactedaccording to GP24 to give the title compound (85LM14) (0.344 g, 25%). ¹HNMR (CDCl₃) δ 0.90-1.0 (m, 6H), 1.15-1.30 (m, 9H), 1.55-1.65 (m, 2H),1.80 (t, 1H), 1.95 (t, 1H), 2.15-2.30 (m, 3H), 2.70 (d, 1H), 2.90 (d,1H), 3.80 (dd, 1H), 4.05 (dd, 1H), 7.10-7.20 (m, 2H), 7.30 (t, 1H), 7.40(d, 1H); HPLC-MS (ammonium acetate) [M+H]⁺=347.3.

3.2033-(3-(4-Propoxy-piperidin-1-yl)-2-methyl-propyl)-3H-benzothiazol-2-one(85LM49B)

4-Propxypiperidine (79KS66) (0.150 g, 0.62 mmol),3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one (85LM13) (0.179 g,0.74 mmol), NaI (0.185 g, 1.2 mmol), and K₂CO₃ (0.172 g, 1.2 mmol) werereacted according to GP24 to give the title compound (85LM49b) (0.049 g,23%). ¹H NMR (CDCl₃) δ 0.90-1.0 (m, 6H), 1.45-1.60 (m, 4H), 1.80-1.90(m, 2H), 2.00 (t, 1H), 2.10-2.30 (m, 4H), 2.60 (m, 1H), 2.80 (m, 1H),3.20 (m, 1H), 3.40 (t, 2H), 3.80 (dd, 1H), 4.00 (dd, 1H), 7.10-7.20 (m,2H), 7.30 (d, 1H), 7.40 (d, 1H); HPLC-MS (ammonium acetate)[M+H]⁺=349.2.

3.204 General Procedure 25 (GP25)

A 100 ml flask, charged with 4-butyl-piperidine (1 equiv),toluene-4-sulfonic acid ester (1 equiv) and K₂CO₃ (1 equiv) in MeCN (20ml), was stirred at 40° C. for 48 hours. Water (20 ml) and EtOAc (20 ml)were added and the phases were separated. The aqueous phase wasre-extracted with EtOAc (20 ml). The combined organic phases were dried(Na₂SO₄) and evaporated to dryness. The crude product was purified by CC(SiO₂; MeOH/DCM 1:50).

3.2053-(3-(4-Butyl-piperidin-1-yl)-(S)-3-hydroxy-2-methyl-propyl)-3H-benzothiazol-2-one(85LM74-62S)

Toluene-4-sulfonic acid (R)-2-methyl-3-(2-oxobenzothiazol-3-yl)-propylester (85LM73-61) (0.900 g, 2.4 mmol), 4-butylpiperidine (0-336 g, 2.4mmol), and K₂CO₃ (0.30 g, 2.4 mmol) were reacted according to GP25 togive the title compound (85LM74-62S) (0.450 g, 24%). ¹H NMR (CDCl₃) δ0.90-1.0 (m, 6H), 1.15-1.30 (m, 9H), 1.55-1.65 (m, 2H), 1.80 (t, 1H),1.95 (t, 1H), 2.15-2.30 (m, 3H), 2.70 (d, 1H), 2.90 (d, 1H), 3.80 (dd,1H), 4.05 (dd, 1H), 7.10-7.20 (m, 2H), 7.30 (t, 1H), 7.40 (d, 1H);HPLC-MS (ammonium acetate) [M+H]⁺=347.3.

3.2063-(3-(4-Butylpiperidin-1-yl)-(R)-3-hydroxy-2-methylpropyl)-3H-benzothiazol-2-one(85LM91-78R)

Toluene-4-sulfonic acid (S)-2-methyl-3-(2-oxo-benzothiazol-3-yl)-propylester (85LM90-77) (0.900 g, 2.4 mmol), 4-butylpiperidine (0-336 g, 2.4mmol), and K₂CO₃ (0.30 g, 2.4 mmol) were reacted according to GP25 togive the title compound (85LM91-78R) (0.450 g, 24%). ¹H NMR (CDCl₃) δ0.90-1.0 (m, 6H), 1.15-1.30 (m, 9H), 1.55-1.65 (m, 2H), 1.80 (t, 1H),1.95 (t, 1H), 2.15-2.30 (m, 3H), 2.70 (d, 1H), 2.90 (d, 1H), 3.80 (dd,1H), 4.05 (dd, 1H), 7.10-7.20 (m, 2H), 7.30 (t, 1H), 7.40 (d, 1H);HPLC-MS (ammonium acetate) [M+H]⁺=347.3.

3.207 General Procedure 26 (GP26)

A mixture of 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (1.2equiv), an amine (1.0 equiv) and K₂CO₃ (2.0 equiv) in MeCN/DCM (1:2, 3mL) was shaken at 40° C. for 15 h. The mixture was cooled to roomtemperature before adding resin bound isocyanate (ArgoNaut TechnologiesInc., PS-isocyanate, 3 equiv) and was then left standing for 18 h.Thereafter filtration through cotton wool was performed and subsequentlypurified by ionexchange (Varian BondElut®-SCX, H⁺). Elution with 2.5%NH₄OH in MeOH and concentration gave the title compounds.

3.2083-[3-(3-Pent-1-ynyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)propyl]-3H-benzothiazol-2-one(79KS38-5)

3-Pent-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-5) (0.033 g, 0.188mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.072 g, 0.226mmol), and K₂CO₃ (0.052 g, 0.376 mmol) were reacted according to GP26 togive the title compound (79KS38-5) (0.018 g, 26%). ¹H NMR (CDCl₃) δ 0.98(t, 3H, J=7.5 Hz, —CH₂CH₂CH ₃), 1.57 (sixt, 2H, J=7.5 Hz, —CH₂CH ₂CH₃),1.59 (ddd, 1H, J=6.8 Hz, 8.3 Hz, J=13.9 Hz), 1.71 (d, 1H, J=18.0 Hz),1.85 (td, 1H, J=3.0 Hz, J=9.0 Hz), 1.89-2.02 (m, 3H), 2.11 (m, 1H), 2.26(t, 2H, J=7.2 Hz, —CH₂CH₂CH ₂—N(from bicyclo[3.2.1]-oct-2-en-8-ylsystem)), 2.53 (m, 1H, J=18.0 Hz), 2.56-2.68 (m, 2H), 3.31 (dd, 1H,J=4.5 Hz, 8.1 Hz), 3.35 (t, 1H, J=5.4 Hz), 4.04 (t, 2H, J=6.8 Hz, N(fromAr)—CH ₂CH₂CH₂—), 6.02 (d, 1H, J=5.6 Hz, H2 (frombicyclo[3.2.1]-oct-2-en-8-yl system), 7.01-7.44 (m, 4H, Ar); ¹³C NMR(CDCl₃): δ 13.7, 21.5, 22.4, 26.7, 29.8, 33.8, 35.4, 41.3, 45.5, 55.6,57.0, 80.7, 89.6, 111.1, 118.5, 122.7, 123.0, 123.1, 126.4, 135.3,137.6, 170.2. HPLC-MS (ammonium acetate): [M+H]⁺=367.31

3.2093-[3-(3-Hex-ynyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)propyl]-3H-benzothiazol-2-one(79KS38-6)

3-Hex-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-6) (0.049 g, 0.259mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.099 g, 0.311mmol) and K₂CO₃ (0.072 g, 0.518 mmol) were reacted according to GP26 togive the title compound (79KS38-6) (0.053 g, 54%). ¹H NMR (CDCl₃) δ 0.90(t, 3H, J=7.0 Hz, —CH ₃), 1.34-1.52 (m, 4H, —CH₂CH ₂CH ₂CH₃), 1.55 (ddd,1H, J=6.6 Hz, 9.0 Hz, 12.1 Hz), 1.66 (d, 1H, J=17.6 Hz), 1.85 (td, 1H,J=2.6 Hz, 10.8 Hz), 1.86-1.97 (m, 3H), 2.06 (m, 1H), 2.26 (t, 2H, J=7.2Hz, —CH₂CH₂CH ₂—N (from bicyclo[3.2.1]-oct-2-en-8-yl system), 2.49 (d,1H, J=17.6 Hz), 2.56 (m, 2H), 3.25 (dd, 1H, J=4.6 Hz, 6.9 Hz), 3.28 (t,1H, J=5.8 Hz), 4.02 (t, 2 Hz, J=5.8 Hz, N(from Ar)—CH ₂CH₂CH₂—), 6.01(d, 1H, J=6.8 Hz, H2(from bicyclo[3.2.1]-oct-2-en-8-yl system); ¹³C NMR(CDCl₃) δ 13.8, 19.2, 22.2, 26.8, 29.3, 31.1, 33.9, 35.4, 41.3, 45.6,55.5, 56.9, 80.7, 89.4, 111.1, 118.4, 122.7, 123.0, 123.1, 126.4, 135.7,137.7, 170.1; HPLC-MS (ammonium acetate): [M+H]⁺=381.32

3.2103-[3-(3-Hept-1-ynyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)propyl]-3H-benzothiazol-2-one(79KS38-7)

3-Hept-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-7) (0.051 g, 0.250mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.096 g, 0.300mmol) and K₂CO₃ (0.069 g, 0.500 mmol) were reacted according to GP26 togive the title compound (79KS38-7) (0.057 g, 58%). ¹H NMR (CDCl₃) δ 0.90(t, 3H, J=7.1 Hz, —CH₂CH₂CH₂CH ₃), 1.24-1.40 (m, 4H), 1.44-1.54 (m, 2H),1.59 (ddd, 1H, J=5.5 Hz, 9.1 Hz, 13.1 Hz), 1.72 (d, 1H, J=18.0 Hz), 1.84(td, 1H, J=2.8 Hz, 8.3 Hz), 1.90-2.06 (m, 3H), 2.06-2.18 (m, 1H), 2.28(t, 2H, J=6.9 Hz, —CH₂CH₂CH ₂—N(from bicyclo[3.2.1]-oct-2-en-8-ylsystem), 2.52 (d, 1H, J=18.0 Hz), 2.64 (m, 2H), 3.26-3.42 (m, 2H), 4.04(t, 2H, J=6.9 Hz, N (from Ar)—CH ₂CH₂CH₂—), 6.02 (d, 1H, J=5.9 Hz),7.06-7.44 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ 14.1, 19.5, 22.4, 26.6, 28.7,29.8, 31.3, 33.8, 35.3, 41.2, 45.5, 55.6, 57.0, 80.5 and 90.0 (sp C's),111.1, 118.6, 122.6, 123.3, 126.4, 137.6 (Ar), 170.2 (C═O); HPLC-MS(ammonium acetate): [M+H]⁺=395.34

3.2113-{3-[3-(4-Hydroxy-but-1-ynyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]propyl}-3H-benzothiazol-2-one(79KS38-2)

4-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-but-3-yn-1-ol (79KS36-2) (0.018 g,0.102 mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.039 g,0.122 mmol) and K₂CO₃ (0.028 g, 0.204 mmol) were reacted according toGP26 to give the title compound (79KS38-2) (0.022 g, 59%). ¹H NMR(CDCl₃) δ 1.56 (ddd, 1H, J=5.9 Hz, 9.3 Hz, 13.2 Hz), 1.67 (d, 1H, J=17.6Hz), 1.83 (td, 1H, J=2.3 Hz, 9.1 Hz), 1.87 (m, 6H), 2.02-2.15 (m, 1H),2.51 (m, 1H, 17.6 Hz), 2.54-2.64 (m, 4H), 3.27 (dd, 1H, J=4.7 Hz, 7.1Hz), 3.31 (t, 1H, J=5.7 Hz), 3.71 (t, 2H, J=6.3 Hz, —CH₂CH ₂OH), 4.04(t, 2H, J=7.0 Hz, N(from Ar)—CH ₂CH₂CH₂—), 6.08 (d, 1H, J=5.6 Hz, H2(from bicyclo[3.2.1]-oct-2-en-8-yl system)), 7.10-7.44 (m, 4H, Ar); ¹³CNMR (CDCl₃) δ 24.0, 26.8, 29.9, 33.8, 35.3, 41.3, 45.7, 55.5, 57.0,61.3, 82.7, 85.4, 111.1, 117.9, 122.7, 123.0, 123.1, 126.4, 136.9,137.7, 170.2. HPLC-MS (ammonium acetate): [M+H]⁺=369.28

3.2123-{3-[3-(5-Hydroxy-pent-1-ynyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]propyl}-3H-benzothiazol-2-one(79KS38-3)

5-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-pent-4-yn-1-ol (79KS36-3) (0.045 g,0.235 mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.090 g,0.282 mmol) and K₂CO₃ (0.065 g, 0.470 mmol) were reacted according toGP26 to give the title compound (79KS38-3) (0.059 g, 66%). ¹H NMR(CDCl₃): δ 1.57 (ddd, 1H, J=6.2 Hz, 9.4 Hz, 13.4 Hz), 1.68 (d, 1H,J=17.9 Hz), 1.72-2.00 (m, 6H), 2.03-2.16 (m, 1H), 2.42 (t, 2H, J=6.9Hz), 2.50 (d, 1H, 17.9 Hz), 2.54-2.63 (m, 2H), 3.28 (td, 1H, J=4.8 Hz,6.9 Hz), 3.74 (t, 2H, J=6.0 Hz, —CH₂CH₂CH ₂OH), 4.40 (t, 2H, J=7.2 Hz, N(from Ar)—CH ₂CH₂CH₂—), 6.04 (d, 1H, J=4.5 Hz), 7.10-7.44 (m, 4H, Ar);¹³C NMR (CDCl₃) δ 16.2, 26.8, 29.9, 31.6, 33.8, 35.3, 41.3, 45.6, 55.5,57.0, 62.0, 81.3, 88.5, 111.1, 118.2, 122.7, 123.0, 123.1, 126.4, 136.0,137.6, 170.2; HPLC-MS (ammonium acetate): [M+H]⁺=383.30

3.2133-[3-(3-Propyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one(79KS83-2)

8-tertButyloxycarbonyl-3-propyl-8-aza-bicyclo[3.2.1]octane (79KS75)(0.012 g, 0.0474 mmol) was dissolved in DCM (2 mL) followed by theaddition of TFA (0.5 mL) under stirring. The mixture was left stirringuntil complete conversion of the starting material had occurred beforeit was concentrated in vacuo, basified (2M NaOH), extracted (EtOAc) andconcentrated once again. The resultant oil was reacted with3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.018 g, 0.0569 mmol)and K₂CO₃ (0.013 g, 0.0948 mmol) in accordance with GP26 to give thetitle compound (79KS83-2) (0.011 g, 67%). ¹H NMR (CDCl₃) δ 0.86 (t, 3H,7.2 Hz, —CH₂CH₂CH ₃), 1.10-1.20 (m, 2H), 1.20-1.42 (m, 4H), 1.42-1.50(m, 2H), 1.50-1.66 (m, 3H), 1.80-1.98 (m, 4H), 2.38-2.50 (m, 2H),3.05-3.15 (m, 2H), 4.05 (t, 2H, J=6.6 Hz, N(from Ar)—CH ₂CH₂CH₂),7.10-7.44 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ 14.5, 20.2, 26.8, 27.9, 37.8,39.4, 41.2, 49.0, 59.8, 111.4, 122.7, 122.9, 123.1, 126.4, 137.7;HPLC-MS (ammonium acetate): [M+H]⁺=377.16

3.2143-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one(79KS96-2)

8-tert-Butyloxycarbonyl-3-butyl-8-aza-bicyclo[3.2.1]octane (79KS92)(0.045 g, 0.168 mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80)(0.064 g, 0.202 mmol) and K₂CO₃ (0.046 g, 0.336 mmol) were reactedaccording to GP26 to give the title compound (79KS96-2) (0.019 g, 32%).¹H NMR (CDCl₃) δ 0.87 (t, 3H, J=7.2 Hz, —CH₂CH₂CH₂CH ₃), 1.12-1.64 (m,13H), 1.80-1.98 (m, 4H), 2.43 (t, 2H, J=6.4 Hz), 3.18 (br s, 2H), 4.05(t, 2H, J=6.3 Hz, N(from Ar)—CH ₂CH₂CH₂), 7.10-7.43 (m, 4H, Ar); ¹³C NMR(CDCl₃) δ 14.3 (—CH₂CH₂CH₂CH₃), 23.1, 26.8, 28.2, 29.4, 36.8, 37.9,41.2, 49.0, 59.7, 111.4, 122.7, 122.9, 123.1, 126.4, 137.7, 170.2 (C═O);HPLC-MS (ammonium acetate): [M+H]⁺=359.27

3.2153-[3-(3-Pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one(79KS97-oxalate)

3-Pentyl-8-aza-bicyclo[3.2.1]octane (79KS95) (0.118 g, 0.651 mmol),3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80) (0.064 g, 0.781 mmol)and K₂CO₃ (0.046 g, 1.30 mmol) were reacted according to GP26 to give(79KS97) (0.161 g, 66%). The oxalate salt was prepared by dissolving theproduct in Et₂O and a minimum of MeOH followed by the addition of asolution of oxalic acid (1.1 eq of obtained product) in Et₂O. Filtrationgave the title compound (79KS97-oxalate). NMR of the free base wasrecorded. ¹H NMR (CDCl₃); δ 0.88 (t, 3H, J=6.9 Hz, —CH₂CH₂CH₂CH₂CH ₃),1.17-1.38 (m, 8H), 1.38-1.48 (m, 2H), 1.56-1.75 (m, 3H), 1.86-2.00 (m,4H), 2.08-2.22 (m, 2H), 2.43 (t, 2H, J=6.7 Hz), 3.18 (br s, 2H), 4.07(t, 2H, J=6.9 Hz, N(from Ar)—CH ₂CH₂CH₂), 7.12-7.43 (m, 4H, Ar); ¹³C NMR(CDCl₃) δ 14.3 (—CH₂CH₂CH₂CH₂CH₃), 22.9, 26.9, 27.3, 28.3, 28.5, 32.2,35.7, 38.6, 41.2, 48.9, 58.9, 111.3, 122.7, 123.0 123.1, 126.4, 137.7,170.2(C═O); HPLC-MS (ammonium acetate): [M+H]⁺=373.28

3.2163-[3-(3-Hexyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one(79KS83-8)

8-tertButyloxycarbonyl-3-hexyl-8-aza-bicyclo[3.2.1]octane (79KS81)(0.031 g, 0.105 mmol), 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80)(0.040 g, 0.126 mmol) and K₂CO₃ (0.029 g, 0.210 mmol) were reactedaccording to GP26 to give the title compound (79KS83-8) (0.035 g, 86%).¹H NMR (CDCl₃) δ 0.82-0.94 (t, 3H, J=6.8 Hz, —CH₂CH₂CH₂CH₂CH₂CH ₃),1.10-1.37 (m, 12H), 1.40-1.62 (m, 5H), 1.80-1.95 (m, 4H), 2.40 (t, 2H,6.2 Hz), 3.18 (br s, 2H), 4.04 (t, 2H, J=6.8 Hz, N(from Ar)—CH ₂CH₂CH₂),7.08-7.44 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ 14.3 (—CH₂CH₂CH₂CH₂CH₂ CH₃),22.9, 26.8, 27.0, 27.1, 28.3, 29.7, 32.1, 37.2, 38.1, 41.3, 49.0, 59.7,111.3, 122.7, 122.9, 123.1, 126.4, 137.8, 170.2(C═O); HPLC-MS (ammoniumacetate): [M+H]⁺=387.27

3.2173-[3-(3-Butylidene-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one(61KS91-1)

To a slurry of butylphosphonium bromide (1.70 g, 4.26 mmol) in dry THF(10 mL) was added BuLi (2.66 mL, 1.6M sol., 4.26 mmol) at 0° C. understirring. The mixture was allowed to reach room temperature and stirredfor another 2 h before dropwise addition of a solution ofN-Boc-nortropinone (0.960 g, 4.26 mmol) in dry THF (5 mL) at 0° C. Thereaction mixture was slowly heated to room temperature and thereafterleft stirring overnight. The resultant heterogeneous mixture wasfiltered and concentration in vacuo followed by column chromatography inDCM to yield the bicyclic amine 32HS95 (0.032 g, 3%). This was thendissolved in DCM/TFA (1:1, 2 mL) and concentrated. To the resultantsyrup was added 2M NaOH (5 mL) and the mixture was extracted (DCM). Thecombined organic phase was dried (Na₂SO₄), filtered and concentrated.This product was reacted with 3-(3-Iodopropyl)-3H-benzothiazol-2-one(61KS80) (0.046 g, 0.145 mmol) and K₂CO₃ (0.033 g, 0.242 mmol) accordingto GP26 to give the title compound (61KS91-1) (0.025 g, 58%). ¹H NMR(CDCl₃) δ 0.88 (t, 3H, J=7.2 Hz, ═CHCH₂CH₂CH ₃), 1.35 (sixt, 2H, J=7.2Hz, ═CHCH₂CH ₂CH₃), 1.43 (t, 1H, J=8.6 Hz), 1.55 (t, 1H, J=8.6 Hz),1.76-1.92 (m, 5H), 1.97 (quint, 2H, J=7.2 Hz), 2.22 (d, 1H, J=14.4 Hz),2.27 (d, 1H, J=14.4 Hz), 2.50-2.64 (m, 3H), 3.24-3.35 (m, 2H), 4.01 (t,2H, 7.0 Hz, N(from Ar)—CH ₂CH₂CH₂), 5.22 (t, 1H, J=7.4 Hz), 7.20-7.42(m, 4H, Ar); HPLC-MS (ammonium acetate): [M+H]⁺=357.40

3.2183-[3-(4-Methoxymethyl-piperidine-1-yl)-propyl]-3H-benzothiazol-2-one(61KS89-oxalate)

To a solution of 1-tertButyloxycarbonyl-4-methoxymethyl-piperidine(61KS83) (0.088 g, 0.385 mmol) in DCM (2 mL) was added TFA (2 mL) understirring. After complete conversion of the starting material the mixturewas basified (2M NaOH) and extracted with DCM. After drying (Na₂SO₄) ofthe combined organic phase, filtering and concentration, the crudeproduct was reacted with 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80)(0.147 g, 0.462 mmol) and K₂CO₃ (0.106 g, 0.770 mmol) to give the titlecompound (61KS89) (0.086 g, 67%). The oxalate salt was prepared bydissolving the product in Et₂O and a minimum of MeOH followed by theaddition of a solution of oxalic acid (1.1 eq of obtained product) inEt₂O. Filtration gave the title compound (61KS89-oxalate). NMR of thefree base was recorded. ¹H NMR (CDCl₃) δ 1.23 (dq, 2H, J=3.9 Hz, 12.1Hz), 1.48-1.63 (m, 1H), 1.64-1.73 (m, 2H), 1.83-1.95 (m, 4H), 2.35 (t,2H, J=6.9 Hz), 2.84 (m, 2H, J=11.8 Hz), 3.19 (d, 2H, J=7.2 Hz, —CH₂OCH₃), 3.30 (s, 3H, —CH₂OCH ₃), 3.97 (t, 2H, J=7.2 Hz, N(from Ar)—CH₂CH₂CH₂), 7.07-7.40 (m, 4H, Ar); ¹³C NMR (CDCl₃): δ 25.3, 29.5, 36.4,41.3, 53.7, 55.7, 59.0, 78.2 (—CH₂OCH₃), 111.0, 122.7, 123.0, 123.1,126.4, 137.6, 170.1 (C═O); HPLC-MS (ammonium acetate): [M+H]⁺=321.36

3.2193-[3-(4-Ethoxymethyl-piperidine-1-yl)-propyl]-3H-benzothiazol-2-one(61KS91-3-oxalate)

To a solution of 1-tertButyloxycarbonyl-4-ethoxymethyl-piperidine(61KS90) (0.071 g, 0.292 mmol) in DCM (2 mL) was added TFA (2 mL) understirring. After complete conversion of the starting material the mixturewas basified (2M NaOH) and extracted with DCM. After drying (Na₂SO₄) ofthe combined organic phase, filtering and concentration, the crudeproduct was reacted with 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80)(0.112 g, 0.350 mmol) and K₂CO₃ (0.067 g, 0.484 mmol) according to GP26to give the title compound (61KS91-3) (0.048 g, 49%). The oxalate saltwas prepared by dissolving the product in Et₂O and a minimum of MeOHfollowed by the addition of a solution of oxalic acid (1.1 eq ofobtained product) in Et₂O. Filtration gave the title compound(61KS91-3-oxalate). NMR of the free base was recorded. ¹H NMR (CDCl₃) δ1.16 (t, 3H, J=7.0 Hz, —CH₂OCH₂CH ₃), 1.41 (dq, 2H, J=4.2 Hz, 12.6 Hz),1.56-1.70 (m, 1H), 1.74-1.82 (m, 2H), 2.05 (quint, 2H, J=7.0 Hz, N(fromAr)—CH₂CH ₂CH₂), 2.13 (td, 2H, J=2.8 Hz, 11.8 Hz), 2.57 (t, 2H, J=7.0Hz, N(from Ar)—CH₂CH₂CH ₂), 3.04 (m, 2H, J=11.2 Hz), 3.22 (d, 2H, J=6.2Hz, —CH ₂OCH₂CH₃), 3.43 (q, 2H, J=7.0 Hz, —CH₂OCH ₂CH₃), 4.00 (t, 2H,J=7.0 Hz, N(from Ar)—CH ₂CH₂CH₂), 7.10-7.40 (m, 4H, Ar); HPLC-MS(ammonium acetate): [M+H]⁺=335.39

3.2203-{3-[4-(2-Methoxyethyl)-piperidine-1-yl]-propyl}-3H-benzothiazol-2-one(61KS91-2-oxalate)

To a solution of 1-tertButyloxycarbonyl-4-(2-methoxyethyl)-piperidine(61KS86) (0.100 g, 0.410 mmol) in DCM (2 mL) was added TFA (2 mL) understirring. After complete conversion of the starting material the mixturewas basified (2M NaOH) and extracted with DCM. After drying (Na₂SO₄) ofthe combined organic phase, filtering and concentration, the crudeproduct was reacted with 3-(3-Iodopropyl)-3H-benzothiazol-2-one (61KS80)(0.157 g, 0.492 mmol) and K₂CO₃ (0.113 g, 0.820 mmol) according to GP26to give the title compound (0.089 g, 65%). The oxalate salt was preparedby dissolving the product in Et₂O and a minimum of MeOH followed by theaddition of a solution of oxalic acid (1.1 eq of obtained product) inEt₂O. Filtration gave the title compound (61KS91-2-oxalate). NMR of thefree base was recorded. ¹H NMR (CDCl₃) δ 1.23 (dq, 2H, J=12.1 Hz),1.31-1.43 (m, 1H), 1.49 (q, 2H, J=6.3 Hz, —CH ₂CH₂OCH₃), 1.62-1.70 (m,2H), 1.85-1.96 (m, 4H), 2.37 (t, 2H, J=7.3 Hz, N(from Ar)—CH₂CH₂CH ₂),2.80-2.88 (m, 2H, J=12.0 Hz), 3.30 (s, 3H, —CH ₂CH₂OCH ₃), 3.38 (t, 2H,J=6.3 Hz, —CH₂CH ₂OCH₃), 3.98 (t, 2H, J=7.3 Hz, N(from Ar)—CH ₂CH₂CH₂),7.08-7.40 (m, 4H, Ar); HPLC-MS (ammonium acetate): [M+H]⁺=335.39

3.221 General Method 27 (GP27)

To a solution of a Boc-protected amine (1.0 eq) in DCM (2 mL) was addedTFA (2 mL) followed by concentration in vacuo. The remaining syrup wasdissolved in MeCN (3 mL) followed by addition of3-(3-Chloropropyl)-3H-benzothiazol-2-one (61KS67) (0.046 g, 0.204 mmol,1.3 equiv), NaI (0.031 g, 0.204 mmol, 1.3 equiv) and Na₂CO₃ (0.083 g,0.7.85 mmol, 5 eq). The reaction mixture was shaken at 80° C. for 18 h.Excess cyclohexyl isocyanate (4.0 equiv) was added and shaking at 80° C.was continued for another 30 min before the reaction mixture was put onan ionexchange column (Varian BondElut®-SCX, H⁺) and eluted with 2.5%NH₄OH in MeOH. Evaporation of the solvent gave the desired product. Thiswas taken up in Et₂O and a solution of oxalic acid (1.1 equiv) in Et₂Owas added. The white precipitate was filtered off and dried. NMR spectraof the free bases were recorded.

3.2223-{3-[4-(Prop-2-ene-1-oxy)-piperidin-1-yl]-propyl}-3H-benzothiazol-2-one(61KS69-oxalate)

1-tert-Butyloxycarbonyl-4-(prop-2-ene-1-oxy)-piperidine (104KS20) (0.038g, 0.157 mmol) was reacted according to GP27 to give the title compound(61KS69-oxalate) (0.040 g, 77%). ¹H NMR (CDCl₃) δ 1.54-1.65 (m, 2H),1.80-1.94 (m, 5H), 2.06 (td, J=2.0 Hz, 11 Hz), 2.36 (t, 2H, 7.0 Hz),2.66-2.75 (m, 2H), 3.34 (sept, 1H, J=4.3 Hz), 3.96-4.04 (m, 4H), 5.14(ddt, 1H, J=1.5 Hz, J=11 Hz, —OCH₂CH═CH _(c)H_(t)), 5.26 (ddt, 1H, J=1.8Hz, 17.6 Hz, —OCH₂CH═CH _(c) H _(t)), 5.91 (ddt, 1H, J=5.5 Hz, 11 Hz,17.6 Hz, —OCH₂CH═CH _(c)H_(t)), 7.10-7.42 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ25.4, 31.7, 41.2, 51.5, 55.2, 69.0 and 74.8 (C4 and—OCH₂CH═CH_(c)H_(t)), 111.0, 116.7, 122.8, 123.0, 123.1, 126.4, 135.6,137.6 (Ar), 170.2 (C═O). HPLC-MS (ammonium acetate): [M+H]⁺=333.35

3.223 3-[3-(4-Propoxy-piperidin-1-yl)-propyl]-3H-benzothiazol-2-one(61KS70-1-oxalate)

1-tert-Butyloxycarbonyl-4-propoxy-piperidine (104KS21) (0.049 g, 0.200mmol) was reacted according to GP27 to give the title compound(61KS70-1-oxalate) (0.056 g, 80%). ¹H NMR (CDCl₃) δ 0.90 (t, 3H, J=7.1Hz, —OCH₂CH₂CH ₃), 1.50-1.63 (m, 4H), 1.82-1.95 (m, 4H), 2.06 (td, 2H,J=2.4 Hz, 10.8 Hz), 2.35 (t, 2H, J=6.8 Hz), 2.70 (dt, 2H, J=4.8 Hz, 8.0Hz), 3.26 (sept, 1H, J=4.3 Hz), 3.37 (t, 2H, J=6.8 Hz), 3.99 (t, 2H,J=7.0 Hz), 7.09-7.42 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ 10.9 (—OCH₂CH₂ CH₃),23.5, 25.3, 31.4, 41.1, 51.4, 55.2, 69.8 and 74.9 (—OCH₂CH₂ CH₃ and C4),111.1, 122.8, 122.9, 123.2, 126.5, 137.5 (Ar), 170.3 (C═O). HPLC-MS(ammonium acetate): [M+H]⁺=335.37

3.224 3-[3-(4-Isobutoxy-piperidin-1-yl)-propyl]-3H-benzothiazol-2-one(61KS70-2-oxalate)

1-tert-Butyloxycarbonyl-4-(isobutoxy)-piperidine (61KS66) (0.051 g,0.200 mmol) was reacted according to GP27 to give the title compound(61KS70-2-oxalate) (0.059 g, 85%). ¹H NMR (CDCl₃) δ 0.89 (d, 6H, J=6.6Hz, —OCH₂CH(CH ₃)₃), 1.52-1.63 (m, 2H), 1.81 (nonet, 1H, J=6.9 Hz,—OCH₂CH(CH₃)₃), 1.82-1.89 (m, 2H), 1.90 (quint, 2H, 7.0 Hz, N(fromAr)—CH₂CH ₂CH₂—), 2.65 (td, 2H, J=2.3 Hz, 10.9 Hz), 2.35 (t, 2H, J=7.0Hz, N(from Ar)—CH₂CH₂CH ₂—), 2.68 (m, 2H), 3.17 (d, 2H, J=6.9 Hz, —OCH₂CH(CH₃)₃), 3.20-3.28 (m, 1H), 3.99 (t, 2H, J=7.0 Hz, N(from Ar)—CH₂CH₂CH₂—), 7.10-7.42 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ 19.7(—OCH₂CH(CH₃)₃), 25.5, 29.0, 31.7, 41.2, 51.5, 55.3, 75.1 and 75.2 (C4and —OCH₂CH(CH₃)₃), 111.0, 122.7, 123.0, 123.1, 126.4, 137.7 (Ar), 170.1(C═O); HPLC-MS (ammonium acetate): [M+H]⁺=349.1

3.2253-[3-(4-Cyclobutylmethoxy-piperidin-1-yl)-propyl]-3H-benzothiazol-2-one(61KS 70-3-oxalate)

1-tert-Butyloxycarbonyl-4-(cyclobutylmethoxy)-piperidine (61KS51) (0.054g, 0.200 mmol) was reacted according to GP27 to give the title compound(61KS70-3-oxalate) (0.044 g, 61%). ¹H NMR (CDCl₃) δ 1.53-1.64 (m, 2H),1.64-1.75 (m, 2H), 1.78-1.97 (m, 5H), 1.98-2.20 (m, 3H), 2.39 (t, 2H,J=6.9 Hz), 2.52 (sept, 1H, J=7.4 Hz, —OCH₂CH(CH₂CH₂CH₂)), 2.67-2.76 (m,2H), 3.22-3.30 (m, 1H), 3.39 (d, 2H, J=7.4 Hz, —OCH ₂CH(CH₂CH₂CH₂), 3.99(t, 2H, J=6.9 Hz), 7.09-7.41 (m, 4H, Ar); ¹³C NMR (CDCl₃) δ 18.8(—OCH₂CH(CH₂ CH₂CH₂)), 25.3 (—OCH₂CH(CH₂CH₂ CH₂)), 31.4, 34.2, 35.6,41.2, 51.4, 55.2, 72.8 and 74.9 (—OCH₂CH(CH₂CH₂CH₂) and C4), 111.1,122.7, 122.9, 123.2, 126.4, 137.6 (Ar), 170.2 (C═O).

3.2261-[3-(1,5-Dioxa-9-azaspiro[5.5]undec-9-yl)propyl]-1,3-dihydrobenzoimidazol-2-one(45NK66)

The reaction was carried out according to GP20 using1,5-dioxa-9-azaspiro[5.5]undecane (59 mg, 0.5 mmol). The product waspurified using an Isco CombiFlash Sq 16× (4.1 g silica column, elutingCH₂Cl₂ (5 min), 0-15% methanol in CH₂Cl₂ (20 min), 15% methanol inCH₂Cl₂ (15 min)). Methanol (2 mL) and HCl in ether (2 M, 0.2 mL) wereadded, the solution concentrated to give the title compound as thehydrochloride salt (14 mg).

¹H NMR (CD₃OD) δ 1.67 (tt, 2H), 1.92 (m, 4H), 1.95 (tt, 2H), 2.46 (m,6H), 3.87 (t, 4H), 3.92 (t, 2H), 7.07 (m, 3H), 7.17 (m, 1H); LC-MS[M+H]⁺ 332.2 (cald. 332.2).

3.227 1-(3-[4-Butylpiperidino]propyl)-1,3-dihydrobenzimidazol-2-one(61KS19)

1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazole-2-one (7.23 g, 34.3mmol), 4-butylpiperidine (3.73 g, 26.4 mmol), NaI (5.14 g, 34.3 mmol)and Na₂CO₃ (3.64 g, 34.3 mmol) was suspended in CH₃CN (200 mL) andrefluxed for 3 h and then cooled to room temperature. Water (100 mL) wasadded followed by extraction (EtOAc), drying (MgSO₄), filtration andconcentration in vacuo. The crude product was purified by columnchromatography [SiO₂, EtOAc/MeOH/NH₄OH (85:10:5) followed by SiO₂,dichloromethane/MeOH (95:5) (R_(f)(3)=0.21)] to give the titled compound(6.26 g, 75%) as a colorless oil, which was converted into thecorresponding oxalate salt.

¹H-NMR (amine, CDCl₃) δ 0.88 (t, 3H, J=6.9 Hz), 1.34-1.14 (m, 9H), 1.65(d, 2H, J=9.2 Hz), 1.86 (t, 2H, J=10.7 Hz), 1.97 (quint, 2H, J=7.3 Hz),2.38 (t, 2H, J=7.6 Hz), 2.86 (d, 2H, J=10.7 Hz), 3.84 (t, 2H, J=7.3 Hz),7.10-7.00 (m, 4H), 10.2 (br s, 1H).

3.228 4-(3-Methylbutylidene)piperidine hydrochloride (18HS64)

Isoamyltriphenylphosphonium bromide (25.0 g, 60.5 mmol) was suspended inanhydrous THF (130 ml) and cooled to 0° C. n-BuLi was added drop wiseover a 1-1.5 h period. The resulting mixture was stirred at roomtemperature for 2 h. Boc-4-piperidone (12.05 g, 60.5 mmol) was dissolvedin anhydrous THF (25 ml) and added in small portions at 30° C. Themixture was left with stirring over night at 30° C. The reaction mixturewas cooled to room temperature. The precipitated triphenylphosphineoxide was filtered off and the crude product was concentrated in vacuo.The crude residue was purified by column chromatography (SiO₂,dichloromethane). Treatment with 2N HCl in dioxane gave the titlecompound in 60% yield.

¹H NMR (CDCl₃) δ 0.85 (d, 6H), 1.57 (n, 1H), 1.86 (t, 2H), 2.49-2.56 (m,4H), 3.12-3.20 (m, 4H), 5.32 (t, 1H), 9.64 (br s, 2H); ¹³C NMR (CDCl₃) δ22.4, 25.2, 28.8, 32.7, 36.5, 45.1, 45.9, 126.2, 130.4.

3.229 1-tert-Butoxycarbonyl-4-butylidenepiperidine (61KS6)

To a slurry of butylphosphonium bromide (748 mg, 1.8 mmol) in drydiethyl ether (10 mL) was added BuLi (1.1 mL, 1.6 M solution, 1.8 mmol)at 0° C. over a period of 5 min. The cooling was removed and thereaction mixture was left stirring for 1 h. A solution of1-tert-butoxycarbonyl-4-piperidone (300 mg, 1.5 mmol) in dry diethylether (5 mL) was carefully added and the stirring was continued for 3 hat room temperature. The reaction was quenched by the addition of water(10 mL) followed by extraction (diethyl ether), drying (MgSO₄),filtration and concentration in vacuo. The crude product was purified bycolumn chromatography (SiO₂, ethyl acetate/heptane (1:6) Rf=0.47) togive the title compound (253 mg) as a colorless oil.

¹H NMR (CDCl₃) δ 0.87 (t, 3H, J=7.0 Hz), 1.34 (2H, J=7.0 Hz), 1.45 (s,9H), 1.96 (dt, 2H, J=7.0 Hz), 2.10 (t, 2H, J=6.2 Hz), 2.18 (t, 2H, J=6.2Hz), 3.36 (dt, 4H, J=6.2 Hz), 5.20 (t, 1H, J=7.0 Hz); ¹³C NMR (CDCl₃) δ13.9, 23.3, 28.5, 28.7, 29.3, 36.1, 79.5, 124.2, 135.2, 155.0.

3.230 1-tert-Butoxycarbonyl-4-pentylidenepiperidine (61KS7)

The reaction was carried out according to the method used for thepreparation of 6]KS-6 using pentylphosphonium bromide to give 50% of thetitle compound.

¹H NMR (CDCl₃) δ 0.89 (t, 3H, J=6.9 Hz), 1.36-1.24 (m, 4H), 1.46 (s,9H), 2.12 (t, 2H, J=6.2 Hz), 2.19 (t, 2H, J=6.2 Hz), 3.38 (dt, 4H, J=6.2Hz), 5.20 (t, 1H, J=7.1 Hz); ¹³C NMR (CDCl₃) δ 14.2, 22.5, 27.0, 28.5,28.7, 32.4, 36.1, 79.6, 124.4, 135.0, 155.1.

3.231 1-(3-[4-Butylidenepiperidino]propyl)-1,3-dihydrobenzimidazol-2-one(61KS12)

1-tert-Butoxycarbonyl-4-butylidenepiperidine (49 mg, 0.2 mmol) wasdissolved in trifluoroacetic acid (2 mL) and left stirring at roomtemperature for 5 min followed by concentration in vacuo. The resultantsyrup was dissolved in acetonitrile (5 mL) and1-(3-chloropropyl)1,3-dihydro-2H-benzimidazole-2-one (58 mg, 0.28 mmol),sodium iodide (41 mg, 0.28 mmol) and Na₂CO₃ (56 mg, 0.53 mmol) was addedand shaken for 3 days at 80° C. Water (5 mL) was added followed byextraction (ethyl acetate), drying (MgSO₄), filtration andconcentration. The crude product was purified by column chromatography[SiO₂, ethyl acetate/methanol/ammonium hydroxide (85:10:5) (R_(f)0.52)followed by SiO₂, dichloromethane/methanol (95:5) (R_(f)0.21)] to givethe title compound (26 mg) as a colorless oil.

¹H NMR (CDCl₃) δ 0.88 (t, 3H, J=7.3 Hz), 1.34 (sext, 2H, J=7.3 Hz),2.03-1.91 (m, 4H), 2.18 (t, 2H, J=5.6 Hz), 2.24 (t, 2H, J=5.6 Hz),2.46-2.35 (m, 6H), 3.97 (t, 2H, J=6.7 Hz), 5.12 (t, 1H, J=7.3 Hz),7.15-7.00 (m, 4H), 10.3 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.9, 23.4, 26.1,28.4, 29.4, 36.2, 39.3, 54.9, 55.5, 55.7, 108.2, 109.8, 121.3, 121.5,122.8, 128.3, 130.8, 136.2, 156.0.

3.2321-(3-f4-Pentylidenepiperidino]propyl)-1,3-dihydrobenzimidazole-2-one(61KS13)

The reaction was carried out according to the method used for thepreparation of 61KS12 using1-tert-butoxycarbonyl-4-pentylidenepiperidine (49 mg, 0.2 mmol) to give60% of the title compound.

¹H NMR (CDCl₃) δ 0.88 (t, 3H, J=6.7 Hz), 1.38-1.23 (m, 4H), 2.04-1.90(m, 4H), 2.17 (t, 2H, J=5.5 Hz), 2.24 (t, 2H, J=5.5 Hz), 2.44-2.33 (m,6H), 3.96 (t, 2H, J=5.5 Hz), 5.12 (t, 1H, J=7.3 Hz), 7.15-6.95 (m, 4H),10.2 (br s, 1H); ¹³C NMR (CDCl₃) δ 14.2, 22.5, 26.1, 27.0, 28.4, 32.5,36.2, 39.3, 54.9, 55.5, 55.7, 108.3, 109.8, 121.3, 121.5, 123.0, 128.3,130.8, 136.0, 155.9.

3.233 3-[3-(4-Butylpiperidin-1-yl)propyl]-3H-benzothiazol-2-one (56NK34)

A 25 ml round bottomed flask was charged with 3H-benzothiazole-2-one(151 mg, 1.0 mmol) and a stirring bar then evacuated and put underargon. THF (5 mL) was added followed by sodium hydride (48 mg of 60%suspension in oil, 1.2 mmol) and the reaction was stirred at 0° C. for90 min. 1-Chloro-3-iodopropane (129 μL, 1.2 mmol) was added and thereaction was stirred for 18 h at room temperature. Water (2 mL) wasadded and the product was extracted into ethyl acetate (2×10 mL). Theorganic layer was dried (K₂CO₃), filtered and concentrated in vacuobefore being purified by using an Isco CombiFlash Sq 16× (4.1 g silicacolumn, eluting 0-35% ethyl acetate in heptanes (30 min) then 35% ethylacetate in heptanes (12 min)) to give a 1:1 mixture of3-(3-chloro-propyl)-3H-benzothiazol-2-one and3-allyl-3H-benzothiazole-2-one (121 mg). A 7 mL vial was charged withthe mixture, 4-butyl-piperidine (75 mg, 0.53 mmol), sodium iodide (159mg, 1.06 mmol), sodium carbonate (112 mg, 1.06 mmol) and acetonitrile (2mL) and shaken at 80° C. for 18 h. The reaction was cooled to roomtemperature and water (2 mL) was added. The product was extracted intoethyl acetate (2×5 mL), the organic layer was dried (K₂CO₃), filteredand concentrated in vacuo before being purified by using an IscoCombiFlash Sq 16× [4.1 g silica column, eluting 0-20% 2-propanol inCH₂Cl₂ (25 min) then 20% 2-propanol in CH₂Cl₂ (30 min)] to give thetitle compound (26 mg).

¹H NMR (CDCl₃) δ 0.89 (t, 3H), 1.16-1.33 (m, 9H), 1.68 (m, 2H), 1.97 (m,4H), 2.42 (t, 2H), 2.90 (br. d, 2H), 4.01 (t, 2H), 7.12-7.20 (m, 2H),7.30 (m, 1H), 7.41 (m, 1H).

3.234 2-(3-Chloropropylthio)benzoxazole (62KK004)

Sodium hydride (0.132 g, 3.3 mmol, 60% in mineral oil) was added inportions to a stirred solution of 2-mercaptobenzoxazole (0.500 g, 3.3mmol) in dry THF (10 ml) under argon at 0° C. After complete additionthe mixture was stirred at room temperature for 1.5 h. A solution of3-chloro-1-iodopropane (0.677 g, 3.31 mmol) in dry THF (1 ml) was addeddropwise and the mixture stirred at room temperature for 24 h. Water waspoured into the reaction mixture, and the aqueous mixture was extractedwith dichloromethane. The combined organic phases was dried (K₂CO₃),filtered and concentrated to give 0.71 g of a brown oil. The oil waspurified by flash chromatography on silica gel using n-heptane anddichloromethane (2/1 and 1/1) as eluent to give 0.604 g of the titlecompound as a colorless oil.

¹H NMR (CDCl₃) δ 2.37-2.31 (m, CH₂), 3.46 (t, J=7, CH₂), 3.72 (t, J=6,CH₂), 7.30-7.21 (m, 2H), 7.45-7.42 (m, 1H), 7.61-7.58 (m, 1H); ¹³C NMR(CDCl₃ δ 29.5, 32.1, 43.2, 110.1, 118.7, 124.2, 124.6, 142.1, 152.1,164.5. MS: 227 (MH⁺).

3.235 2-(3-Chloropropylthio)benzothiazole (62KK005)

The reaction was carried out according to the method used for thepreparation of 62KK004 using 2-mercaptobenzothiazole (0.12 g, 3.0 mmol)to give 76% of the title compound. The crude oil was purified by flashchromatography on silica gel using n-heptane and CH₂Cl₂ (1/1) as eluentto give 0.552 g of the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ 2.36-2.29 (m, CH₂), 3.51 (t, J=7, CH₂), 3.71 (t, J=6,CH₂), 7.32-7.26 (m, 1H), 7.43-7.39 (m, 1H), 7.76-7.74 (m, 1H), 7.88-7.85(m, 1H); ¹³C-NMR (CDCl₃) δ 30.7, 32.2, 43.4, 121.2, 121.8, 124.6, 126.3,135.5, 153.5, 166.3: MS: 244 (MH⁺).

3.236 2-(2-Chloroethylthio)benzoxazole (56NK27)

Sodium hydride (0.048 g, 1.2 mmol, 60% in mineral oil) was added inportions to a stirred solution of 2-mercaptobenzoxazole (0.151 g, 1.00mmol) in dry THF (5 ml) under argon at 0° C. After complete addition themixture was stirred at room temperature for 1.5 h. A solution of3-chloro-1-iodoethane (0.228 g, 1.2 mmol) was added and the mixturestirred at room temperature for 24 h. Water was poured into the reactionmixture, and the aqueous mixture was extracted with dichloromethane. Thecombined organic phases was dried (K₂CO₃), filtered and concentrated togive 0.101 g of the title compound as an oil.

¹N-NMR (CDCl₃) δ 3.63 (t, J=7, CH₂), 3.93 (t, J=7, CH₂), 7.32-7.23 (m,2H), 7.46-7.43 (m, 1H), 7.61-7.59 (m, 1H).

3.237 2-[3-(4-Butyl-1-piperidinyl)propylthio]benzoxazole (62KK034)

A 7 mL vial was charged with 4-butylpiperidine (0.028 g, 0.20 mmol),2-(3-chloropropylthio)benzoxazole (0.050 g, 0.22 mmol), sodium iodide(0.035 g, 0.23 mmol), and K₂CO₃ (0.030 g, 0.22 mmol) and 1 mlacetonitrile and shaken at 50° C. for 18 h. Water was added and theaqueous mixture was extracted with dichloromethane. The combined organicphases was filtered through a polytetrafluoroethylene membrane and thenconcentrated to give 0.064 g of a crude oil. Dichloromethane (2 ml) andPS-Isocyanate (1.0-1.5 mmol/g) resin (0.050 g) were added and theresulting mixture was left at room temperature for 2 h and thenfiltered. The resin was washed with dichloromethane, and the combinedorganic phases was concentrated to give 0.051 g oil. The oil wasdissolved in methanol and loaded onto a Varian SCX ion exchange column.The column was washed with methanol (2 column volumes) then the productwas eluted off the column using 10% ammonium hydroxide in methanol (2column volumes). The solute was concentrated to give the title compound(0.021 g) as a colorless oil.

¹H-NMR (CDCl₃) δ 0.88 (t, J=7 Hz, CH₃), 1.31-1.21 (m, 9H), 1.67-1.64 (m,2H), 1.93-1.88 (m, 2H), 2.06-1.99 (m, CH₂), 2.47 (t, J=7 Hz, CH₂),2.91-2.88 (m, 2H), 3.35 (t, J=7 Hz, CH₂), 7.29-7.20 (m, 2H), 7.43-7.41(m, 1H), 7.59-7.57 (M, 1H); ¹³C-NMR (CDCl₃) δ 14.3, 23.1, 27.0, 29.2,30.7, 32.7, 36.0, 36.5, 54.3, 57.6, 110.0, 118.6, 123.9, 124.4, 142.3,152.1, 165.4. MS: 333 (MH⁺).

3.238 2-[3-(4-butyl-1-piperidinyl)propylthio]benzothiazole (62KK003)

A 7 mL vial was charged with 4-butylpiperidine (0.028 g, 0.20 mmol),2-(3-chloropropylthio)benzothiazole (0.054 g, 0.22 mmol), sodium iodide(0.034 g, 0.23 mmol), K₂CO₃ (0.031 g, 0.22 mmol) and acetonitrile (2 ml)and shaken at 82° C. for 20 h. Water was added and the aqueous mixturewas extracted with dichloromethane. The combined organic phases wasdried (K₂CO₃), filtered and concentrated to give 0.068 g of a crude oil.The crude oil (0.040 g) was purified with preparative RP-HPLC [SYNARGI60 mm×21.2 mm. 20 ml/min, gradient acetonitrile/H₂O (10 mM ammoniumacetate)] to afford 0.016 g of the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ 0.81 (t, J=7, CH₃), 1.22-1.14 (m, 9H), 1.60-1.57 (m,2H), 1.86-1.80 (m, 2H), 1.98-1.91 (m, CH₂), 2.40 (t, J=7, CH₂),2.84-2.81 (m, 2H), 3.31 (t, J=7, CH₂), 7.23-7.19 (m, 1H), 7.35-7.31 (m,1H), 7.68-7.66 (m, 1H), 7.79-7.77 (m, 1H); MS: 349 (MH⁺).

3.239 2-[2-(4-butyl-1-piperidinyl)ethylthio]benzoxazole (62KK004)

The reaction was carried out according to the method used for thepreparation of 62KK003 using crude 2-(2-chloroethylthio)-benzoxazole(0.098 g) to give 0.034 g of the title compound as a colorless oil.

¹H-NMR (CDCl₃) 0.81 (t, J=7, CH₃), 1.22-1.14 (m, 9H), 1.60-1.58 (m, 2H),1.97-1.92 (m, 2H), 2.69 (t, J=7, CH₂), 2.89-2.86 (m, 2H), 3.39 (t, J=7,CH₂), 7.21-7.12 (m, 2H), 7.36-7.33 (m, 1H), 7.52-7.50 (m, 1H); ¹³C-NMR(CDCl₃) δ 14.3, 23.1, 29.2, 30.5, 32.6, 35.9, 36.5, 54.1, 57.6, 110.0,118.6, 123.9, 124.4, 142.3, 152.1, 165.6; MS: 319 (MH⁺).

1. A compound of Formula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is selected from the group consisting of C, O, N and S; Z is selected from the group consisting of CH and N; Y is selected from the group consisting of ═O, ═N and ═S or tautomers thereof; —SPU— is a biradical selected from the group consisting of —(CR⁶R⁷)_(n)-A- and —C₃₋₈-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5; A is absent or an optionally substituted —C₃₋₈-cycloalkyl; N together with R¹ and R² form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R⁴ selected from the group consisting of halogen, C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₆-alkyloxyimino, and C₁₋₆-alkyloxyamino each of which may be optionally substituted with a substituent R⁵, and wherein at least one of said substituents R⁴ is R^(4′) selected from the group consisting of C₁₋₈-alkyl, C₃₋₈-cycloalkyl, C₁₋₈-alkoxy, C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, each of which may be optionally substituted with a substituent R⁵; R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, C₁₋₈-alkyl, C₁₋₈-alkoxy, C₃₋₈-cycloalkyl, C₃₋₈-heterocyclyl, C₁₋₈-alkylcarbonyl, C₁₋₈-alkylidene, C₂₋₈-alkenyl and C₂₋₈-alkynyl; R^(X) may be absent or selected from the group consisting of hydrogen, optionally substituted C₁₋₈-alkyl, optionally substituted C₃₋₈-cycloalkyl, optionally substituted C₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl, CH₂—N(R⁵)(R⁵), CH₂—OR⁵, CH₂—SR⁵, and CH₂—O—C(═O)R⁵; R³ may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C₁₋₈-alkyl, C₁₋₈-alkoxy, optionally substituted C₁₋₈-alkylidene, optionally substituted C₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl, and optionally substituted C₁₋₈-alkylcarbonyl; and each R⁶ and each R⁷ is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C₁₋₈-alkyl, C₁₋₈-alkoxy, optionally substituted C₁₋₈-alkylidene, optionally substituted C₂₋₈-alkenyl, optionally substituted C₂₋₈-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C₃₋₈-cycloalkyl, optionally substituted C₃₋₈-heterocyclyl, and optionally substituted C₁₋₈-alkylcarbonyl.
 2. The compound of claim 1, wherein Z is N.
 3. The compound of claim 2, wherein X is selected from the group consisting of N, S, and O.
 4. The compound of claim 3, wherein —Y is ═O.
 5. The compound of claim 1, wherein R4′ is selected from the group consisting of C₁₋₈-alkyl, C₁₋₈-alkoxy, C₃₋₈-cycloalkyl, C₁₋₈-alkylidene, each of which may be optionally substituted with a substituent R⁵.
 6. The compound of claim 1, wherein R⁴ is selected from the group consisting of C₃₋₈-alkyl, C₃₋₈-alkoxy, and C₃₋₈-alkylidene, each of which may be optionally substituted with a substituent R⁵ wherein R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy and C₁₋₈-alkyl.
 7. The compound of claim 1, wherein R⁴ is selected from the group consisting of an optionally substituted butyl, an optionally substituted pentyl, an optionally substituted propyloxy, and 3-(C₁₋₈-alkyl)-butylidene.
 8. The compound of claim 1, selected from the group consisting of: 1-(3-[4-Butylpiperidino]propyl)-1,3-dihydrobenzimidazol-2-one, 1-(3-[4-Butylidenepiperidino]propyl)-1,3-dihydrobenzimidazol-2-one, 1-[3-(4-Pentylpiperidin-1-yl)propyl]-1,3-dihydrobenzoimidazol-2-one, 1-(3-[4-Pentylidenepiperidino]propyl)-1,3-dihydrobenzimidazole-2-one, 1-{3-[4-(3-Methylbutylidene)piperidin-1-yl]propyl}-1,3-dihydrobenzoimidazol-2-one, and 1-[3-(4-Butylpiperidin-1-yl)propyl]-3-methyl-1,3-dihydrobenzoimidazol-2-one.
 9. The compound of claim 1, selected from the group consisting of: 3-[3-(4-Butylpiperidin-1-yl)propyl]-3H-benzothiazol-2-one, 3-{3-[4-(Prop-2-ene-1-oxy)-piperidin-1-yl]-propyl}-3H-benzothiazol-2-one, 3-[3-(4-Propoxy-piperidin-1-yl)-propyl]-3H-benzothiazol-2-one, 3-[3-(3-Butylidene-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one, 3-(3-(4-Butyl-piperidin-1-yl)-2-methyl-propyl)-3H-benzothiazol-2-one, 3-(3-(4-Propoxy-piperidin-1-yl)-2-methyl-propyl)-3H-benzothiazol-2-one, 3-(3-(4-Butylpiperidin-1-yl)-(R)-2-methylpropyl)-3H-benzothiazol-2-one, 3-[3-(4-butylpiperidin-1-yl]propyl)-4-methyl-3H-benzooxazol-2-one, 3-[3-(4-butylpiperidin-1-yl)propyl)-5-methyl-3H-benzooxazol-2-one, 3-[3-(4-butylpiperidin-1-yl)propyl]-5-fluoro-3H-benzooxazol-2-one, 3-[3-(4-butylpiperidin-1-yl)propyl]-6-fluoro-3H-benzooxazol-2-one, 1-(3-(4-Butylpiperidin-1-yl)propyl)-1,3-dihydro-indol-2-one, 3-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one, and 3-[3-(3-Pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-benzothiazol-2-one
 10. A pharmaceutical composition comprising a compound according to claim 1, together with pharmaceutically acceptable carriers or excipients.
 11. A method of treating mental disease or disorder in a mammal comprising identifying a mammal in need thereof and administering at least one compound of claim 1 to said mammal.
 12. The method of claim 11, wherein the mental disorder is selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, sleep disorders, and psychosis.
 13. The method of claim 11, wherein the mental disorder is selected from the group consisting of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, and sudden infant death syndrome.
 14. A method of treating a disease or disorder associated with increased intraocular pressure in a mammal comprising identifying a mammal in need thereof and administering at least one compound of claim 1 to said mammal.
 15. A method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of claim
 1. 16. The method of claim 15, wherein the compound is a cholinergic agonist.
 17. The method of claim 15, wherein the compound is selective for one or both of a M₁ and M₄ muscarinic receptor subtypes.
 18. The method of claim 15, wherein the compound further acts as a D₂ antagonist or D₂ inverse agonist.
 19. A method of treating pain in a mammal, comprising administering an effective amount of a compound of claim 1 to said mammal.
 20. A method of prophylactic or curative treatment of psychosis or alleviation of symptoms of psychosis in a mammal, comprising administering an effective amount of a compound of claim 1 to said mammal.
 21. A method of modulating the progression or formation of amyloid plaques in an individual susceptible to or affected by Alzheimer's Disease, comprising administering an effective amount of a compound of claim 1, said effective amount sufficient to modulate amyloid precursor protein processing. 